Dosage regimens for and compositions including Anti-RSV antibodies

Abstract

To provide methods of treating or preventing RSV infection in a patient in need thereof.SOLUTION: The present invention provides dosing regimens for administering a composition including a fixed dose of an anti-RSV monoclonal antibody or an antigen binding fragment thereof. The present invention also provides pharmaceutical compositions for the treatment or prevention of RSV infection, and a pharmaceutical unit dose including nirsevimab.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 840,701, filed April 30, 2019, which is incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically to the United States Patent and Trademark Office via EFS-Web as an ASCII text file entitled "0490-000006WO01_ST25.txt" created on April 29, 2020, with a size of 24 kilobytes. The electronically submitted Sequence Listing serves as both the paper copy required by 37 CFR § 1.821(c) and the CRF required by 37 CFR § 1.821(e) since the Sequence Listing has been electronically filed. The information contained in the Sequence Listing is incorporated herein by reference. [Background technology]

[0003] Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants and children worldwide. Nearly all children will be infected with RSV during the first 2 years of life. In 2005, RSV was responsible for more than 30 million new cases of lower respiratory tract infections among children aged 5 years or younger, with an estimated 66,000 to 199,000 deaths worldwide.

[0004] While all children are at risk for severe lower respiratory tract infection during their initial infection, healthy term infants aged 3 months or younger experience more RSV-related hospitalizations than any other group. Severe disease during infancy can lead to acute and long-term pulmonary sequelae, including recurrent episodes of wheezing throughout childhood.

[0005] Currently, the only approved prophylaxis against RSV disease is palivizumab (SYNAGIS; MedImmune, Gaithersburg, MD). Palivizumab is an RSV fusion (F)-specific immunoglobulin G monoclonal antibody indicated for the prevention of severe RSV lower respiratory tract disease in high-risk children, including preterm infants born at 35 weeks gestation or less. In part due to the high cost of prophylactic administration of palivizumab, current guidance from the American Academy of Pediatrics does not recommend it for healthy preterm infants born at 29 weeks gestation or more. Furthermore, a safe and effective active vaccine remains elusive. Thus, additional tools for RSV prophylaxis, especially for use in healthy term infants, would be advantageous. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure describes methods, including administration regimens, pharmaceutical compositions, and pharmaceutical unit doses of anti-RSV antibodies or fragments thereof, for treating or preventing RSV infection in a patient.

[0007] In one aspect, the disclosure describes a method of treating or preventing a RSV infection in a patient in need thereof.

[0008] In some embodiments, the method of treating or preventing a RSV infection in a patient in need thereof includes determining the age of the patient. For patients in their second year of life, the method includes administering a fixed dose of 200 milligrams (mg) of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof. For patients in their first year of life, the method includes determining the patient's weight, and for patients weighing at least 5 kilograms (kg), the method includes administering a fixed dose of 100 mg of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof.

[0009] In some embodiments, a method for treating or preventing a RSV infection in a patient in need thereof comprises administering a fixed dose of 200 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient weighing at least 5 kg.

[0010] In some embodiments, a method of treating or preventing a RSV infection in a patient in need thereof includes determining the patient's weight and administering a fixed dose of 200 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient weighing at least 5 kg, or administering a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient weighing up to 5 kg.

[0011] In some embodiments, a patient weighing at least 5 kg weighs up to 10 kg, up to 15 kg, or up to 20 kg.

[0012] In some embodiments, a method of treating or preventing a RSV infection in a patient in need thereof includes determining the age of the patient and administering a fixed dose of 200 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient 3 months of age or older.

[0013] In some embodiments, a method of treating or preventing a RSV infection in a patient in need thereof includes determining the age of the patient and administering a fixed dose of 200 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient 6 months of age or older.

[0014] In some embodiments, a method of treating or preventing a RSV infection in a patient in need thereof includes determining the age of the patient and administering a fixed dose of 200 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient 3 months of age or older, or administering a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient up to 3 months of age.

[0015] In some embodiments, a method of treating or preventing a RSV infection in a patient in need thereof includes determining the age of the patient and administering a fixed dose of 200 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient 6 months of age or older, or administering a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient up to 6 months of age.

[0016] In some embodiments, a method of treating or preventing a RSV infection in a patient in need thereof includes determining whether the patient is experiencing a first or second RSV season. For patients experiencing a second RSV season, the method includes administering a fixed dose of 200 milligrams (mg) of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof. For patients experiencing a first RSV season, the method includes determining the patient's body weight; and for patients having a body weight of at least 5 kilograms (kg), administering a fixed dose of 100 mg of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof.

[0017] In some embodiments, a method of treating or preventing a RSV infection in a patient in need thereof includes determining whether the patient is experiencing a first RSV epidemic or a second RSV epidemic; and administering to the patient experiencing a second RSV epidemic a fixed dose of 200 milligrams (mg) of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof.

[0018] In some embodiments, a method of treating or preventing a RSV infection in a patient in need thereof includes determining whether the patient is experiencing a first or second RSV season. If the patient is experiencing a second RSV season, the method includes administering to the patient a fixed dose of 200 milligrams (mg) of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof. If the patient is experiencing a first RSV season, the method includes administering to the patient a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof (wherein the patient is experiencing a first RSV season).

[0019] In some embodiments, the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in a RSV B9320 neutralization assay, or both.

[0020] In some embodiments, the anti-RSV monoclonal antibody comprises nirsevimab. In some embodiments, the antigen-binding fragment of the anti-RSV monoclonal antibody comprises an antigen-binding fragment of nirsevimab.

[0021] In some embodiments, the method may include administering the anti-RSV monoclonal antibody or antigen-binding fragment thereof as a composition. In some embodiments, the composition includes an ionic excipient, a buffer, a sugar, and / or a surfactant. In some embodiments, the ionic excipient includes L-arginine hydrochloride at a concentration of 80 mM. In some embodiments, the buffer includes 30 mM L-histidine / L-histidine hydrochloride. In some embodiments, the sugar includes 120 mM sucrose. In some embodiments, the surfactant includes polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v). In some embodiments, the composition may have a pH in the range of 5.5 to 6.5. In some embodiments, the anti-RSV monoclonal antibody or antigen-binding fragment thereof may be present in the composition at a concentration of 100 mg / mL.

[0022] In another aspect, the present disclosure describes a pharmaceutical composition for the treatment or prevention of RSV infection. In some embodiments, the pharmaceutical composition may comprise 100 mg of nirsevimab, and the composition may be administered to a patient in the first year of life, the patient having a body weight of at least 5 kg. In some embodiments, the pharmaceutical composition may comprise 200 mg of nirsevimab, and the composition may be administered to a patient in the second year of life.

[0023] In some embodiments, after administration of the pharmaceutical composition, the patient has an AUC 0-∞ Shows.

[0024] In some embodiments, the pharmaceutical composition comprises an ionic excipient, a buffer, a sugar, and / or a surfactant. In some embodiments, the ionic excipient comprises L-arginine hydrochloride at a concentration of 80 mM. In some embodiments, the buffer comprises 30 mM L-histidine / L-histidine hydrochloride. In some embodiments, the sugar comprises 120 mM sucrose. In some embodiments, the surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v). In some embodiments, the composition may have a pH in the range of 5.5 to 6.5. In some embodiments, the nirsevimab may be present in the composition at a concentration of about 100 mg / ml.

[0025] In yet another aspect, the present disclosure describes a pharmaceutical unit dose comprising nirsevimab. In some embodiments, the pharmaceutical unit dose comprises 100 mg of nirsevimab. In some embodiments, the pharmaceutical unit dose comprises 200 mg of nirsevimab. In some embodiments, the unit dose is suitable for intramuscular administration.

[0026] In some embodiments, the pharmaceutical unit dose comprises a composition comprising nirsevimab. In some embodiments, the composition comprises an ionic excipient, a buffer, a sugar, and / or a surfactant. In some embodiments, the ionic excipient comprises L-arginine hydrochloride at a concentration of 80 mM. In some embodiments, the buffer comprises 30 mM L-histidine / L-histidine hydrochloride. In some embodiments, the sugar comprises 120 mM sucrose. In some embodiments, the surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v). In some embodiments, the composition may have a pH in the range of 5.5 to 6.5. In some embodiments, the nirsevimab may be present in the composition at a concentration of about 100 mg / ml.

[0027] In some embodiments, nirsevimab in the composition is stable for at least 3 months at 2°C to 8°C as measured by high performance size exclusion chromatography (HPSEC).

[0028] As used herein, the term "antibody" or "immunoglobulin" refers to a tetrameric glycoprotein consisting of two heavy chains and two light chains, each containing a variable region and a constant region. Antigen-binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. The term "antibody" includes monoclonal antibodies, polyclonal antibodies, chimeric antibodies, human antibodies, and humanized antibodies.

[0029] As used herein, the term "antibody" or "antigen-binding fragment thereof" includes artificial antibodies, such as monoclonal antibodies (mAbs) and / or antigen-binding fragments thereof, produced by conventional hybridoma technology, by phage display, and / or by recombinant technology. These terms include both intact immunoglobulin molecules, including, for example, polyclonal antibodies, monoclonal antibodies (mAbs), monospecific antibodies, bispecific antibodies, multispecific antibodies, as well as portions, fragments, regions, peptides, and derivatives thereof (provided by any known technique, including, but not limited to, enzymatic cleavage, peptide synthesis, or recombinant technology), such as, for example, immunoglobulins lacking light chains, Fab, Fab', F(ab')2, Fv, scFv, antibody fragments, diabodies, Fd, CDR regions, or any portion or peptide sequence of an antibody capable of binding to an antigen or epitope. The antibody or antigen-binding fragment thereof may be a human antibody, a humanized antibody, an animal antibody (e.g., a camelid antibody), or a chimeric antibody. In one embodiment, the "antigen-binding fragment thereof" is a single chain antibody, a single chain variable fragment (scFv), a Fab fragment, or a F(ab')2 fragment.

[0030] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible minor naturally occurring mutations.

[0031] The terms "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims.

[0032] Unless otherwise specified, "a," "an," "the," and "at least one" are used interchangeably and mean one or more.

[0033] Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (eg, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0034] In methods disclosed herein that include distinct steps, the steps may be performed in any order practicable, and any combination of two or more steps may be performed simultaneously, if desired.

[0035] The above summary of the invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The following description more particularly illustrates exemplary embodiments. In several places throughout this application, guidance is provided by lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

[0036] All headings are for the convenience of the reader and should not be used to limit the meaning of the material that follows the heading, unless so specified.

[0037] Throughout this specification, references to "one embodiment," "an embodiment," "particular embodiments," or "some embodiments" or the like mean that the particular features, configurations, compositions, or characteristics described in connection with the embodiments are included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification do not necessarily refer to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0038] Unless otherwise indicated, all numerical values ​​used in the specification and claims, such as amounts of ingredients, molecular weights, and the like, should be understood in all instances to be modified by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0039] Notwithstanding that the numerical ranges and parameters setting forth the broad invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible, however, all numerical values ​​inherently contain ranges necessarily resulting from the standard deviation found in their respective testing measurements. [Brief description of the drawings]

[0040] [Figure 1] [FIGS. 1A-1B] Figures 1A-1B show the nucleotide sequence of the light chain of nirsevimab (SEQ ID NO: 11) and translation (SEQ ID NO: 1). The CDRs are underlined and the boundary between the variable and constant regions is indicated by "|". [Diagram 2] [FIGS. 2A-2C] Figures 2A-2C show the heavy chain nucleotide sequence (SEQ ID NO: 12) and translation (SEQ ID NO: 2) of nirsevimab. The CDRs are underlined and the boundaries between the variable and constant regions are indicated by "|". The positions of three amino acid substitutions (M252Y / S254T / T256E; "YTE") in the CH2 region of the Fc domain that were introduced to extend the serum half-life of nirsevimab are circled. [Diagram 3]Figure 3 shows a schematic of the Phase 2b study design, as further described in Example 1. ADA = anti-drug antibodies, IM = intramuscular, LRTI = lower respiratory tract infection, PK = pharmacokinetics. PK and ADA samples were collected during screening, days 91, 151, 361, and upon hospitalization for LRTI. Safety assessments were performed from screening through day 361. *Screening and Day 1 visits occur on the same day. [Figure 4] Figure 4 shows the overall incidence of lower respiratory tract infections requiring medical attention during the 150 days following dosing, as further described in Example 1. LRTI = lower respiratory tract infection, RSV = respiratory syncytial virus. [Diagram 5] 5 shows a Kaplan-Meier plot of time to first medically-visited RSV-confirmed LRTI over 150 days post-dose, as further described in Example 1. LRTI = lower respiratory tract infection, No = number, RSV = respiratory syncytial virus. P values ​​were obtained from stratified log-rank and Wilcoxon tests stratified on the two stratification factors (age and hemisphere at randomization). [Figure 6] [FIGS. 6A-6B] Figures 6A-6B show forest plots for subgroup analysis of incidence of RSV-confirmed LRTI (observed) requiring medical attention during the 150 days following dosing, as further described in Example 1. CI = confidence interval, LRTI = lower respiratory tract infection, RRR = relative risk reduction, RSV = respiratory syncytial virus. [Figure 7] FIG. 7 shows an exemplary population pharmacokinetic (popPK) analysis workflow diagram, as further described in Example 2. [Figure 8] FIG. 8 shows a schematic diagram of an exemplary population pharmacokinetic (popPK) structural model. [Figure 9] [Figure 9A] Figure 9A shows postmenstrual ages of infants exposed to nirsevimab in Phase 1b / 2a and Phase 2b. [Figure 9B] Figure 9B shows baseline weight distributions of infants exposed to nirsevimab in Phase 1b / 2a and Phase 2b. [Figure 10]The distribution of available PK data by study is shown: Study 1 - Phase 1 study in healthy adult volunteers (Griffin et al. 2017, Antimicrob Agents Chemother. 61(3), pii:e01714-16); Study 2 - Phase 1b / 2a study in healthy preterm infants with gestational age (GA) 32-35 weeks (Domachowske et al. Pediatr Infect Dis J. 2018;37(9):886-892); and Study 3 - Phase 2b study in healthy preterm infants with GA 29-35 weeks (Example 1). [Figure 11] FIG. 11 shows the effect of size and maturation on the systemic clearance of nirsevimab. [Figure 12] FIG. 12 shows goodness of fit plots of: observed vs. individual predicted nirsevimab concentrations (left panel), and observed vs. population predicted nirsevimab concentrations (right panel). [Figure 13] [Figures 13A-13C] Figures 13A-13C show diagnostic plots of conditional weighted residuals. Figure 13A shows population predicted nirsevimab concentrations (mcg / mL). Figure 13B shows time (days) after administration. Figure 13C shows density of conditional weighted residuals. [Figure 14] FIG. 14 shows a visual prospective check of infant PK data by scheduled visit. [Figure 15] Figure 15 shows a Kaplan-Meier plot of the outcome of medically-accepted respiratory syncytial virus-confirmed lower respiratory tract infection (MALRTI) in the Phase 2b study stratified by AUC quartiles. AUC0-∞=area under the concentration-time curve from time 0 to infinity, MALRTI=medicinal respiratory syncytial virus-confirmed lower respiratory tract infection, Q=quartile. The figure shows data for only subjects in the As-treated population who had at least one detectable post-dose nirsevimab serum concentration. [Figure 16]Figure 16 shows visual predictive checks (VPCs) for MALRTI by geographic region (left panel, north; right panel, south). The lines shown reflect the estimates observed in the placebo group, in the serum AUC 1st quartile, and in infants in the serum AUC ≥2 quartile. The boxes around each line indicate the model predicted 95% confidence intervals around the median for each stratum. [Figure 17] FIG. 17 shows a forest plot of the covariate effects in the final hazard model. [Figure 18] The distribution of quartiles of exposure across all ages and body weights is shown. AUC0-∞ = area under the concentration-time curve from time 0 to infinity, Q = quartile. The figure shows data for only subjects in the As-treated population who had at least one detectable post-dose nirsevimab serum concentration. The horizontal solid line at 5 kg and the vertical dashed lines at 3 and 6 months highlight the differences in Q1 distribution between the various age and body weight ranges. [Figure 19] Figure 19 shows the effect of weight and age on exposure and efficacy. Nirsevimab efficacy in subjects in the lowest AUC quartile was not different from placebo, with the Q2-Q4 AUC range being the target for in vivo clinical efficacy. [Figure 20] Figure 20 shows the predicted AUC distribution of proposed doses of nirsevimab in the Phase 2b >5 kg population to match the exposures observed at up to 5 kg during the initial RSV epidemic. AUC = area under the concentration-time curve. Numbers above the x-axis refer to the number of subjects in each category. Predicted AUC values ​​are estimated as the ratio of dose to total body clearance for all infants as derived from population PK model estimates. The predicted AUC distribution in pink highlights the predicted exposures for 360 infants in the Phase 2b population weighing ≥5 kg when administered 50 mg (test dose) versus 100 mg (proposed) nirsevimab. The yellow box plot shows the AUC distribution for infants in the Phase 2b population weighing <5 kg. The figure shows data for only subjects in the As-treated population who had at least one detectable post-dose nirsevimab serum concentration. [Figure 21]Figure 21 shows the distribution of age and weight of hypothetical infants in the Phase 3 and Phase 2 / 3 populations of the initial RSV epidemic. All hypothetical infants weighed 1.5 kg or had a gestational age (GA) >34 weeks at the time of dosing. Dosing was a flat dose of 50 mg IM single dose or 100 mg IM single dose. Boxes represent interquartile range (25th to 75th percentile) and upper and lower error bars indicate maximum values ​​within 1.5 times the 75th or 25th percentile, respectively. [Figure 22] FIG. 22 shows predicted AUC for hypothetical infants in the first RSV epidemic phase 3 and phase 2 / 3 populations. All hypothetical infants weighed 1.5 kg or had a gestational age (GA) >34 weeks at the time of dosing. Dosing was a fixed dose of 50 mg IM or a single dose of 100 mg IM. The dotted line indicates the target AUC threshold of 13.4 days·mg / mL. Boxes represent interquartile ranges (25th to 75th percentiles) and upper and lower error bars indicate maximum values ​​within 1.5 times the 75th or 25th percentiles, respectively. [Figure 23] Figure 23 shows the age and weight distribution of hypothetical infants in the population during phase 2 / 3 of the second RSV pandemic. Dose is a single fixed dose of 200 mg IM. Boxes represent interquartile ranges (25th to 75th percentiles), and upper and lower error bars indicate maximum values ​​within 1.5 times the 75th or 25th percentiles, respectively. [Figure 24] Figure 24 shows the predicted AUC for a hypothetical infant in the Phase 2 / 3 population during the second RSV pandemic. Dose is a single fixed dose of 200 mg IM. The dotted line indicates the target AUC threshold of 13.4 day·mg / mL. Boxes represent the interquartile range (25th to 75th percentile), and upper and lower error bars indicate the maximum value within 1.5 times the 75th or 25th percentile, respectively. [Diagram 25]FIG. 25 shows in vitro neutralization of RSV A2 (left panel) and RSV B9320 (right panel) by various antibodies, including nirsevimab (1G7), 1F5, 2D10, and D25, each of which inhibited RSV A2 and RSV B9320 as measured by microneutralization assay. [Figure 26] FIG. 26 shows in vitro neutralization of RSV A2 (left panel) and RSV B9320 (right panel) by various antibodies, including D25, nirsevimab (1G7), and variants of nirsevimab (1G7-GLM, B12-1, E3-5, and E9-2), as measured by microneutralization assay (c+v = cells + virus). [Figure 27] [FIG. 27A-27B] Figures 27A-27B show the effect of birth month on the age of an exemplary patient during an RSV epidemic in the United States. Figure 27A shows that a patient born in April (shown by the open arrow) may experience a second RSV epidemic in October of the year of birth (shown by the filled arrow at approximately 7 months of age). Figure 27B shows that a patient born in June (shown by the open arrow) may experience a first RSV epidemic at approximately 7 months of age (shown by the filled arrow). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The present disclosure describes methods, including administration regimens, pharmaceutical compositions, and pharmaceutical unit doses of anti-RSV antibodies or fragments thereof for treating or preventing RSV infection in a patient. In some embodiments, the anti-RSV antibody or fragment thereof comprises nirsevimab (also known as MEDI8897) or a fragment thereof.

[0042] In one aspect, the present disclosure describes a dosing regimen for an anti-RSV antibody or antigen-binding fragment thereof. In particular, the dosing regimen provides a fixed dose to a patient based on age or weight or both.

[0043] In some embodiments, the anti-RSV antibody or antigen-binding fragment thereof comprises a monoclonal antibody, or an antigen-binding fragment of a monoclonal antibody. In some embodiments, the anti-RSV antibody or antigen-binding fragment thereof has an IC50 value of up to 10 ng / ml in an in vitro neutralization assay. In an exemplary in vitro neutralization assay, HEp-2 cells are infected with RSV and the antibody or antigen-binding fragment thereof. In some embodiments, the IC50 is at least 1 ng / ml, at least 2 ng / ml, at least 3 ng / ml, at least 4 ng / ml, at least 5 ng / ml, at least 6 ng / ml, at least 7 ng / ml, or at least 8 ng / ml, for example, for RSV A subtypes including RSV A2. In some embodiments, the IC50 is up to 9 ng / ml, up to 8 ng / ml, up to 7 ng / ml, up to 6 ng / ml, up to 5 ng / ml, up to 4 ng / ml, up to 3 ng / ml, or up to 2 ng / ml, for example, for RSV subtypes including RSV A2. In some embodiments, the IC50 is at least 1 ng / ml, at least 2 ng / ml, at least 3 ng / ml, at least 4 ng / ml, at least 5 ng / ml, at least 6 ng / ml, at least 7 ng / ml, or at least 8 ng / ml, for example against RSV B subtypes, including RSV B9320. In some embodiments, the IC50 is up to 9 ng / ml, up to 8 ng / ml, up to 7 ng / ml, up to 6 ng / ml, up to 5 ng / ml, up to 4 ng / ml, up to 3 ng / ml, or up to 2 ng / ml, for example against RSV B subtypes, including RSV B9320. In one embodiment, the IC50 is measured in an in vitro neutralization assay, for example as described in Examples 3 and / or 4, including for RSV A2 and / or RSV B9320.

[0044] In some embodiments, the anti-RSV antibody or antigen-binding fragment thereof includes a human antibody or antigen-binding fragment thereof. The use of human antibodies for human treatment can reduce the risk of side effects caused by the immunological reaction of human individuals to non-human sequences. In another embodiment, the antibody or antigen-binding fragment thereof can be humanized. In another embodiment, the anti-RSV antibody or antigen-binding fragment thereof can be a chimeric antibody or antigen-binding fragment thereof.

[0045] In some embodiments, the anti-RSV antibody or antigen-binding fragment thereof may have an IgG, IgA, IgM, or IgE isotype. In one embodiment, the anti-RSV antibody or antigen-binding fragment thereof has an IgG isotope.

[0046] In some embodiments, the anti-RSV antibody or antigen-binding fragment thereof has a low or neutral isoelectric point (pI), i.e., the pH at which the protein has no net charge. In some embodiments, the pI of the anti-RSV antibody or antigen-binding fragment thereof is at pH 5.5, at least pH 6, at least pH 6.3, or at least pH 6.4.

[0047] In some embodiments, the pI of the anti-RSV antibody or antigen-binding fragment thereof is up to pH 6.7, up to pH 7, or up to pH 7.5. In exemplary embodiments, the anti-RSV monoclonal antibody or antigen-binding fragment thereof can have a pI in the pH range of, for example, about 5.5 to about 7.5. In exemplary embodiments, the anti-RSV antibody or antigen-binding fragment thereof can have a pI in the range of pH 6.4 to pH 6.7. In one embodiment, the anti-RSV antibody or antigen-binding fragment thereof has a pI of pH 6.4. In some embodiments, the anti-RSV antibody or antigen-binding fragment thereof comprises nirsevimab (also known as MEDI8897) or an antigen-binding fragment of nirsevimab. Nirsevimab is a recombinant human immunoglobulin (Ig) G1 kappa (κ) monoclonal antibody derived from D25. Nirsevimab neutralizes RSV by binding to a highly conserved neutralizing epitope on the pre-fusion structure of the RSV F protein. This binding prevents the RSV F protein from mediating fusion between the viral and cellular membranes, an essential step for viral entry.

[0048] Nirsevimab has a full-length light chain amino acid sequence (SEQ ID NO: 1) as shown in FIG. 1, and a full-length heavy chain amino acid sequence (SEQ ID NO: 2) as shown in FIG. 2.

[0049] Nirsevimab has the following CDR sequences: light chain CDR-L1 of QASQDIVNYLN (SEQ ID NO: 3), light chain CDR-L2 of VASNLET (SEQ ID NO: 4), light chain CDR-L3 of QQYDNLPLT (SEQ ID NO: 5), heavy chain CDR-H1 of DYIIN (SEQ ID NO: 6), heavy chain CDR-H2 of GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and heavy chain CDR-H3 of ETALVVSETYLPHYFDN (SEQ ID NO: 8). In Figures 1 and 2, the six CDRs are underlined.

[0050] Nirsevimab has a light chain variable sequence of amino acid residues 1 to 107 of Figure 1 (SEQ ID NO: 9) and a heavy chain variable sequence of amino acid residues 1 to 126 of Figure 2 (SEQ ID NO: 10).

[0051] The nucleotides encoding the amino acids of the full-length light chain of nirsevimab are also shown in Figure 1 (SEQ ID NO:11).

[0052] The nucleotides encoding the amino acids of the full-length heavy chain of nirsevimab are also shown in Figure 2 (SEQ ID NO:12).

[0053] Nirsevimab is encoded by the RSV mAb 1G7 pOE YTE vector, which was deposited with the American Type Culture Collection (ATCC®), 10801 University Boulevard, Manassas, Va. 20110-2209, USA, under ATCC Patent Accession Number PTA-125141, on September 21, 2018. This deposit is in accordance with the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.

[0054] The nirsevimab-containing vector RSV mAb 1G7 pOE was deposited on September 21, 2018 at the American Type Culture Collection (ATCC®), 10801 University Boulevard, Manassas, Va. 20110-2209, USA, under ATCC Patent Accession Number PTA-125140. This deposit is in accordance with the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.

[0055] Nirsevimab binds to a highly conserved epitope on RSV F and neutralizes a diverse panel of RSV A and B strains with over 50-fold greater activity than palivizumab. At comparable serum concentrations, prophylactic administration of nirsevimab is 9-fold more potent than palivizumab and reduces lung viral load by over 3 logs in cotton rats infected with RSV A or RSV B subtypes (Zhu et al. Sci Transl Med. 2017;9(388).pii:eaaj1928). The nirsevimab antibody is modified with three amino acid changes (M257Y / S259T / T261E [YTE]) in the crystallizable region of a highly conserved fragment. The YTE modifications increase the serum half-life (t 1 / 2 ) is extended beyond the typical 21-28 days. In a Phase 1 placebo-controlled study in healthy adults, nirsevimab had a favorable safety profile, with a mean t 1 / 2The duration of infection extended from 85 to 117 days, and levels of RSV neutralizing antibodies detected in serum increased beyond 150 days (Griffin et al. Antimicrob Agents Chemother. 2016;61:e01714-e01716).

[0056] In a Phase 1b / 2a dose-escalation study, healthy preterm infants with gestational ages 32 to 35 weeks were randomized to receive a single intramuscular injection of nirsevimab (10 mg, 25 mg, or 50 mg) or placebo and found that nirsevimab had a favorable safety profile in healthy preterm infants and helped protect against RSV for a typical 5-month season after a single intramuscular (IM) dose of 50 mg (Domachowske et al. Pediatr Infect Dis J. 2018;37(9):886-892).

[0057] Pharmacokinetic data from a phase 1b / 2a trial of nirsevimab showed that a single 50 mg dose produced antibody concentrations predictive of protection from RSV disease that were maintained for at least 5 months in the majority of infants (Domachowske et al. Pediatr Infect Dis J. 2018;37(9):886-892).

[0058] In some embodiments, the anti-RSV monoclonal antibody or antigen-binding fragment of the anti-RSV monoclonal antibody may comprise a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 1 (the light chain sequence of nirsevimab), and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 2 (the heavy chain sequence of nirsevimab). In some embodiments, the anti-RSV monoclonal antibody may comprise a sequence comprising SEQ ID NO: 1 and / or SEQ ID NO: 2.

[0059] In some embodiments, the anti-RSV monoclonal antibody or antigen-binding fragment of an anti-RSV monoclonal antibody is a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QASQDIVNYLN (SEQ ID NO:3); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence VASNLET (SEQ ID NO:4); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QQYDNLPLT (SEQ ID NO:5); a sequence which is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence DYIIN (SEQ ID NO:6); a sequence which is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence GIIPVLGTVHYGPKFQG (SEQ ID NO:7);and / or may comprise a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence ETALVVSETYLPHYFDN (SEQ ID NO:8);

[0060] In some embodiments, the anti-RSV monoclonal antibody or antigen-binding fragment of an anti-RSV monoclonal antibody may include QASQDIVNYLN (SEQ ID NO: 3), VASNLET (SEQ ID NO: 4), QQYDNLPLT (SEQ ID NO: 5), DYIIN (SEQ ID NO: 6), GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and / or ETALVVSETYLPHYFDN (SEQ ID NO: 8).

[0061] In some embodiments, an anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody may comprise a light chain variable region CDR sequence or a heavy chain variable region CDR sequence that differs from the corresponding CDR sequence of nirsevimab by one amino acid. In some embodiments, an anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody may comprise a light chain variable region CDR sequence or a heavy chain variable region CDR sequence that differs from the corresponding CDR sequence of nirsevimab by two amino acids.

[0062] In some embodiments, the anti-RSV monoclonal antibody or antigen-binding fragment of an anti-RSV monoclonal antibody may comprise a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:9, and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:10.

[0063] Unexpectedly, and as further described in the Examples of the present disclosure, population pharmacokinetic and exposure-response analyses of all pooled pharmacokinetic data in healthy adults and infants (see Griffin et al. 2017, Antimicrob Agents Chemother. 61(3), pii:e01714-16; Domachowske et al. Pediatr Infect Dis J. 2018;37(9):886-892; and Example 1), as well as efficacy data from a Phase 2b study in infants of various degrees of prematurity (see Example 1), demonstrated that 50 mg IM administration of nirsevimab maintained protective serum concentrations of nirsevimab throughout the RSV season, although reduced efficacy was observed in heavier infants.

[0064] In the phase 2b study, the target serum concentration of 6.8 μg / mL was selected based on an RSV challenge study in cotton rats, a model that has proven to be a reliable predictive model for target concentrations and is also used for dose selection of palivizumab. In the phase 2b study, the 50 mg IM dose was selected based on a population-PK model used to identify a dose that would maintain nirsevimab serum concentrations above 6.8 μg / mL throughout the 5-month RSV season. And, in fact, Domachowske et al. reported that pharmacokinetic data from a phase 1b / 2a study of nirsevimab demonstrated that a single 50 mg dose maintained antibody serum concentrations above 6.8 μg / mL for at least 5 months in the majority of infants (Pediatr Infect Dis J. 2018;37(9):886-892).

[0065] However, data analysis and modeling were completed using data from a Phase 2b study using a fixed dose of 50 mg, which demonstrated a clinically meaningful AUC 0-∞ A new exposure target of 13.4 day·mg / mL was defined. AUC efficacious in 97% of infants weighing less than 5 kg was achieved with a dose of 50 mg. 0-∞ The exposure target of 13.4 mg / mL was achieved, but the 50 mg dose was suboptimal in >59% of infants weighing ≥5 kg.

[0066] Further modeling (see Example 2) indicates that different fixed doses (including, for example, weight-based dosing) ensure adequate dosing to maintain nirsevimab serum concentrations above the target AUC that was demonstrated to be clinically effective in a Phase 2b study throughout the RSV season. These doses are as follows: a single fixed dose of 50 mg IM for infants up to 5 kg entering their first RSV season; a single fixed dose of 100 mg IM for infants weighing 5 kg or more entering their first RSV season; and a single fixed dose of 200 mg IM for infants entering their second RSV season. The weight of the majority of infants in their second year of life at the time of dosing is expected to be in the range of 10 kg to 15 kg.

[0067] Method of administration In one aspect, the disclosure provides a method of treating or preventing a RSV infection in a patient in need thereof.

[0068] In some embodiments, the method includes determining the age of the patient. For example, it can be determined whether the patient is in the first year of life or the second year of life. In some embodiments, the patient's age can be at least 1 month, at least 3 months, at least 6 months, at least 12 months (i.e., 1 year). In some embodiments, the patient's age can be up to 1 year or up to 2 years.

[0069] In some embodiments, determining the age of the patient includes determining the gestational age of the patient. For example, in some embodiments, the patient may have a gestational age of at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks, at least 28 weeks, at least 29 weeks, at least 30 weeks, at least 31 weeks, at least 32 weeks, at least 33 weeks, at least 34 weeks, at least 35 weeks, at least 36 weeks, at least 37 weeks, at least 38 weeks, or at least 39 weeks. In an exemplary embodiment, the patient may have a gestational age of at least 29 weeks.

[0070] In some embodiments, the method includes determining whether the patient is experiencing their first or second RSV season. For example, in the United States, where the start of the RSV season ranges from mid-September to mid-November and the end of the season ranges from mid-April to mid-May, a patient born in April may experience their second RSV season in October of the year of birth (approximately 7 months of age) (see FIG. 27A), while a patient born in June may experience their first RSV season in December of the same year (also approximately 7 months of age) (see FIG. 27B).

[0071] In some embodiments, the patient experiencing a first RSV epidemic may be at least 1 month, at least 3 months, or at least 6 months of age, hi some embodiments, the patient experiencing a second RSV epidemic is at least 6 months and up to 2 years of age.

[0072] In some embodiments, the method includes determining the patient's weight. For example, in some embodiments, the patient's weight may be at least 4 kilograms (kg), at least 5 kg, at least 6 kg, at least 7 kg, at least 8 kg, at least 9 kg, or at least 10 kg. In some embodiments, the patient's weight may be up to 5 kg, up to 6 kg, up to 7 kg, up to 8 kg, up to 9 kg, up to 10 kg, up to 11 kg, up to 12 kg, up to 13 kg, up to 14 kg, up to 15 kg, up to 16 kg, up to 17 kg, up to 18 kg, up to 19 kg, or up to 20 kg. In an exemplary embodiment, the patient's weight may be at least 5 kg and up to 20 kg.

[0073] In some embodiments, the patient may have chronic lung disease (CLD). Premature infants are at high risk for CLD due to immaturity of the lungs at birth and lung damage resulting from treatments such as the use of ventilators and / or high oxygen concentrations. Infants with CLD are at particular risk for illness from RSV infection (Carpenter et al. 2004 Pediatr Infect Dis J. 23(1 Suppl):S33-40).

[0074] In some embodiments, the patient may have congenital heart disease. In some embodiments, the CHD may include hemodynamically significant CHD, which may adversely affect pulmonary blood flow. Children with hemodynamically significant CHD have higher rates of RSV-related hospitalization (Boyce et al. 2000 J Pediatr. 137(6):865-870), and children with CHD hospitalized with RSV are at high risk of needing intensive care and mechanical ventilation (Altman et al. 2000 Pediatr Cardiol. 21(5):433-438).

[0075] In some embodiments, the patient may have Down's syndrome. It has been reported that children with Down's syndrome are at significantly higher risk of severe RSV infection than children without Down's syndrome (Beckhaus et al., Pediatrics 2018; 142(3): e20180225).

[0076] In some embodiments, the patient may exhibit immunodeficiency. The immunodeficiency may be primary immunodeficiency or acquired immunodeficiency. Some studies have reported that RSV infection may be more frequent or more severe in infants with congenital or acquired immunodeficiency (including, for example, infants with HIV infection or hematopoietic stem cell and solid organ transplant recipients) than in healthy infants (see, for example, Lanari et al., J Immunol Res.2014;2014:850831).

[0077] In some embodiments, the method includes administering a composition comprising a fixed dose of an anti-RSV antibody or antigen-binding fragment thereof, such as nirsevimab or an antigen-binding fragment thereof. In some embodiments, the fixed dose of the anti-RSV antibody or antigen-binding fragment thereof may include a 50 mg dose, a 100 mg dose, a 150 mg dose, a 200 mg dose, a 250 mg dose, or a 300 mg dose.

[0078] In some embodiments, the methods include administering the composition according to the age and / or weight of the patient.

[0079] For example, in an exemplary embodiment, the method may include administering a composition comprising a fixed dose of 200 mg of nirsevimab, corresponding to the patient being in the second year of life.

[0080] In another exemplary embodiment, the method may include administering a composition comprising a fixed dose of 200 mg of nirsevimab, corresponding to a patient weight of at least 5 kg.

[0081] In an exemplary embodiment, the method may include administering a composition comprising a fixed dose of 50 mg or 100 mg of an anti-RSV antibody or antigen-binding fragment thereof to a patient in the first year of life, depending on the patient's weight. For example, a composition comprising a fixed dose of 50 mg of nirsevimab may be administered to a patient weighing up to 5 kg. Additionally or alternatively, a composition comprising a fixed dose of 100 mg of nirsevimab may be administered to a patient weighing at least 5 kg.

[0082] In another exemplary embodiment, the method may include administering a fixed dose of 200 mg of a composition comprising an anti-RSV antibody or antigen-binding fragment thereof to a patient 3 months of age or older.

[0083] In a further exemplary embodiment, the method may include determining the age of the patient and administering a fixed dose of 200 mg of a composition comprising an anti-RSV antibody or antigen-binding fragment thereof to patients 3 months of age or older, and administering a fixed dose of 100 mg of a composition comprising an anti-RSV antibody or antigen-binding fragment thereof to patients up to 3 months of age.

[0084] In a further exemplary embodiment, the method may include determining the patient's weight and administering a fixed dose of 200 mg of a composition comprising an anti-RSV antibody or antigen-binding fragment thereof to a patient weighing at least 5 kg, and administering a fixed dose of 100 mg of a composition comprising an anti-RSV antibody or antigen-binding fragment thereof to a patient weighing up to 5 kg.

[0085] In some embodiments, the methods include administering the composition depending on the RSV season the patient is experiencing (i.e., a first RSV season or a second RSV season) and / or the patient's weight.

[0086] For example, in an exemplary embodiment, a method may include administering a composition comprising a fixed dose of 100 mg of nirsevimab to a patient experiencing a first RSV flu season.

[0087] In another exemplary embodiment, the method may include administering a composition comprising a fixed dose of 200 mg of nirsevimab to a patient experiencing a second RSV pandemic.

[0088] In further exemplary embodiments, the method may include determining the patient's RSV season and the patient's body weight. The method further includes administering a fixed dose of 100 mg of a composition comprising an anti-RSV antibody or antigen-binding fragment thereof to a patient experiencing a first RSV season and weighing at least 5 kg, and administering a fixed dose of 200 mg of a composition comprising an anti-RSV antibody or antigen-binding fragment thereof to a patient experiencing a second RSV season. In some embodiments, the method further includes administering a fixed dose of 50 mg of a composition comprising an anti-RSV antibody or antigen-binding fragment thereof to a patient experiencing a first RSV season and weighing up to 5 kg.

[0089] In some embodiments, the dose may be administered at the beginning of the RSV season. For example, in the United States, the start of the RSV season ranges from mid-September to mid-November, the peak season ranges from late December to mid-February, and the end of the season ranges from mid-April to mid-May (Rose et al. 2018 MMWR Morb Mortal Wkly Rep. 67:71-76). Lower latitudes, such as Florida, have an earlier RSV season and a longer duration than most parts of the country. (Ibid.). In contrast, most of the Southern Hemisphere generally experiences RSV between May and September, but in tropical or subtropical climates, RSV epidemics are often associated with the rainy season (Sricharoenchai et al. 2016 J Hum Virol Retrovirol 3(1):00076).

[0090] In some embodiments, the dose may be administered parenterally. In some embodiments, the dose may be administered intramuscularly.

[0091] In some embodiments, the patient has an AUC of greater than 10 day·mg / mL, greater than 11 day·mg / mL, greater than 12 day·mg / mL, greater than 13 day·mg / mL, or greater than 14 day·mg / mL 0-∞ In a preferred embodiment, the patient has an AUC of greater than 13.4 day·mg / mL. 0-∞ As further described in Example 2, doses of nirsevimab that result in a serum AUC of greater than 13.4 day mg / mL over a typical 5-month RSV season are expected to provide optimal protection against RSV in infants during the first year of life and in high-risk children during the first 2 years of life.

[0092] In some embodiments, the method includes prophylactically administering a composition comprising an anti-RSV antibody or antigen-binding fragment thereof to prevent or delay the onset of RSV infection. Prophylactic treatment may be initiated before a patient develops symptoms of RSV infection. Administration may occur before, during, or after diagnosis or onset of symptoms of RSV infection. Treatment may be initiated after onset of symptoms to reduce the severity of RSV symptoms or eliminate RSV symptoms altogether.

[0093] The administration of the composition comprising the anti-RSV antibody or antigen-binding fragment thereof can occur before, during, or after other treatments. Such combination therapy can include administration of the anti-RSV antibody or antigen-binding fragment thereof during and / or after the use of another antiviral compound. The administration of the anti-RSV antibody or antigen-binding fragment thereof can occur hours, days, or even weeks after the administration of the other agent.

[0094] composition In another aspect, the present disclosure describes a composition comprising an anti-RSV antibody or an antigen-binding fragment thereof. In some embodiments, the composition comprises nirsevimab or an antigen-binding fragment thereof. In some embodiments, the composition comprises a therapeutically effective amount of an anti-RSV antibody or an antigen-binding fragment thereof. In some embodiments, the composition may comprise a formulation as described in WO 2018 / 160722 A1. In some embodiments, the composition comprises a pharmaceutical composition. The pharmaceutical composition may further comprise a pharma- ceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and / or adjuvant. Additionally, the present disclosure provides a method of treating a patient by administering such a pharmaceutical composition.

[0095] In certain embodiments, acceptable materials included in the composition are non-toxic to recipients at the dosages and concentrations used. In certain embodiments, pharmaceutical compositions may contain formulation materials to modify, maintain or preserve, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or permeability of the composition. In such embodiments, suitable formulation materials include amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrate, phosphate, or other organic acids); bulking agents (such as mannitol, or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides, disaccharides, and other carbohydrates (such as glucose, sucrose, mannose, or dextrin); proteins (such as serum albumin, gelatin, or immunoglobulins); colorants, flavorings, and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; These include, but are not limited to, salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (such as glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (e.g., pluronic, PEG, sorbitan esters (such as polysorbate 20, polysorbate 80), triton, tromethamine, lecithin, cholesterol, tyloxapol); stability enhancers (such as sucrose or sorbitol); tonicity enhancers (e.g., alkali metal halides, sodium or potassium chloride, mannitol, sorbitol, etc.); delivery vehicles; diluents; excipients; and / or pharmaceutical adjuvants.

[0096] Suitable vehicles or carriers may be water for injection, saline, or artificial cerebrospinal fluid. In some embodiments, the vehicle or carrier may be supplemented with other materials common in parenteral compositions. Neutral buffered saline or saline mixed with serum albumin are also examples of additional vehicles.

[0097] In some embodiments, the composition includes a buffer. Exemplary buffers include a Tris buffer of pH 7.0-8.5, an acetate buffer of pH 4.0-5.5, or a histidine buffer of pH 5.5-7.4. In some embodiments, the composition includes histidine or histidine hydrochloride, or a mixture thereof. When the buffer includes an amino acid (e.g., histidine), the amino acid or amino acid salt may include a biologically active form of the amino acid (e.g., the L-form). In some embodiments, the buffer may be included at a concentration of at least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at least 100 mM, at least 110 mM, at least 120 mM, at least 130 mM, at least 140 mM, or at least 150 mM. In some embodiments, the buffer may be included at a concentration of up to 50 mM, up to 60 mM, up to 70 mM, up to 80 mM, up to 90 mM, up to 100 mM, up to 110 mM, up to 120 mM, up to 130 mM, up to 140 mM, up to 150 mM, or up to 160 mM. In an exemplary embodiment, the buffer includes 30 mM L-histidine / L-histidine hydrochloride.

[0098] In some embodiments, the composition may include a humectant, including, for example, sorbitol, or a suitable substitute thereof.

[0099] The formulation components may be included in a concentration that is acceptable to the site of administration. In certain embodiments, a buffer may be used to maintain the composition at physiological pH or slightly below physiological pH. In some embodiments, the pH of the composition may be at least 5, at least 5.1, at least 5.2, at least 5.3, at least 5.4, at least 5.5, at least 5.6, at least 5.7, at least 5.8, at least 5.9, at least 6.0, at least 6.1, at least 6.2, at least 6.3, at least 6.4, at least 6.5, at least 6.6, at least 6.7, at least 6.8, at least 6.9, at least 7.0, at least 7.1, at least 7.2, at least 7.3, at least 7.4, at least 7.5, at least 7.6, at least 7.7, at least 7.8, or at least 7.9. In one embodiment, the pH of the composition can be up to 5.1, up to 5.2, up to 5.3, up to 5.4, up to 5.5, up to 5.6, up to 5.7, up to 5.8, up to 5.9, up to 6.0, up to 6.1, up to 6.2, up to 6.3, up to 6.4, up to 6.5, up to 6.6, up to 6.7, up to 6.8, up to 6.9, up to 7.0, up to 7.1, up to 7.2, up to 7.3, up to 7.4, up to 7.5, up to 7.6, up to 7.7, up to 7.8, up to 7.9, or up to 8.0. In an exemplary embodiment, the pH of the composition can be in the range of 5-8. In an exemplary embodiment, the pH of the composition may range from 5.5 to 6.5. In an exemplary embodiment, the pH of the composition may be 6.0.

[0100] In some embodiments, the composition may include an ionic excipient. An ionic excipient may be included in the antibody formulation to change the charge state of the antibody in the formulation, to change the distribution of the antibody in the formulation, and / or to colloidally stabilize the antibody in the formulation. In some embodiments, the ionic excipient may include a charged amino acid, such as, for example, lysine and / or arginine. In some embodiments, the ionic excipient may include a salt, including, for example, arginine hydrochloride (arginine-HCl), lysine hydrochloride (lysine-HCl), or sodium chloride (NaCl). In some embodiments, the amino acid or amino acid salt may include a biologically active form of the amino acid (e.g., the L-form). In some embodiments, an ionic excipient may be included at a concentration of at least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at least 100 mM, at least 110 mM, at least 120 mM, at least 130 mM, at least 140 mM, or at least 150 mM. In some embodiments, an ionic excipient may be included at a concentration of up to 50 mM, up to 60 mM, up to 70 mM, up to 80 mM, up to 90 mM, up to 100 mM, up to 110 mM, up to 120 mM, up to 130 mM, up to 140 mM, up to 150 mM, or up to 160 mM. In one embodiment, the ionic excipient may be included in a concentration ranging from 50 mM to 150 mM. In one embodiment, the ionic excipient may be included in a concentration ranging from 75 mM to 100 mM. In one embodiment, the ionic excipient may include L-arginine hydrochloride present at a concentration of 75 mM or 80 mM.

[0101] In some embodiments, a composition comprising an anti-RSV antibody or antigen-binding fragment thereof may further comprise a sugar, including, for example, sucrose. In some embodiments, the composition may comprise up to 0.5% (w / v) sucrose, up to 1% (w / v) sucrose, up to 5% (w / v) sucrose, up to 10% (w / v) sucrose, or up to 15% (w / v) sucrose. In some embodiments, the sugar may be present at a concentration of at least 50 mM, at least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at least 100 mM, at least 110 mM, at least 120 mM, at least 130 mM, at least 140 mM, or at least 150 mM. In some embodiments, sugar may be included at a concentration of up to 60 mM, up to 70 mM, up to 80 mM, up to 90 mM, up to 100 mM, up to 110 mM, up to 120 mM, up to 130 mM, up to 140 mM, up to 150 mM, or up to 160 mM. In an exemplary embodiment, sugar includes sucrose at a concentration ranging from 100 mM to 140 mM. For example, the composition may include sucrose at a concentration of 120 mM.

[0102] In some embodiments, the composition comprising an anti-RSV antibody or antigen-binding fragment thereof may further comprise a surfactant, including, for example, a polysorbate. The polysorbate may include, for example, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the surfactant may be present at a concentration of 0.0001% (w / v), at least 0.001% (w / v), at least 0.002% (w / v), at least 0.01% (w / v), at least 0.02% (w / v), at least 0.03% (w / v), at least 0.04% (w / v), at least 0.05% (w / v), at least 0.06% (w / v), at least 0.07% (w / v), at least 0.08% (w / v), at least 0.09% (w / v), or at least 0.1% (w / v). In some embodiments, the surfactant may be included at a concentration of up to 0.0001% (w / v), up to 0.0005% (w / v), up to 0.001% (w / v), up to 0.002% (w / v), up to 0.01% (w / v), up to 0.02% (w / v), up to 0.03% (w / v), up to 0.04% (w / v), up to 0.05% (w / v), up to 0.06% (w / v), up to 0.07% (w / v), up to 0.08% (w / v), up to 0.09% (w / v), or up to 0.1% (w / v). For example, in exemplary embodiments, the surfactant may be present in a concentration ranging from 0.001% (w / v) to 0.5% (w / v), from 0.002% (w / v) to 0.1% (w / v), or from 0.01% (w / v) to 0.05% (w / v). In exemplary embodiments, polysorbate 80 is present in a concentration ranging from 0.01% (w / v) to 0.05% (w / v). In a further exemplary embodiment, 0.02% (w / v) polysorbate 80 is present in the composition. In another exemplary embodiment, 0.04% (w / v) polysorbate 80 is present in the composition.

[0103] In some embodiments, the anti-RSV antibody or antigen-binding fragment thereof may be at a concentration of at least 50 mg / mL, at least 60 mg / mL, at least 70 mg / mL, at least 80 mg / mL, at least 90 mg / mL, at least 100 mg / mL, at least 110 mg / mL, at least 120 mg / mL, at least 130 mg / mL, at least 140 mg / mL, or at least 150 mg / mL. In some embodiments, the anti-RSV antibody or antigen-binding fragment thereof may be at a concentration of up to 60 mg / mL, up to 70 mg / mL, up to 80 mg / mL, up to 90 mg / mL, up to 100 mg / mL, up to 110 mg / mL, up to 120 mg / mL, up to 130 mg / mL, up to 140 mg / mL, up to 150 mg / mL, or up to 160 mg / mL. In an exemplary embodiment, the anti-RSV antibody or antigen-binding fragment thereof may be present at a concentration of about 100 mg / ml to about 165 mg / ml. In an exemplary embodiment, nirsevimab may be at a concentration of 100 mg / mL.

[0104] In some embodiments, the composition may be stored at -20°C to -70°C.

[0105] In some embodiments, the compositions may be stored at 2°C to 8°C. In some embodiments, the formulations described herein are stable for extended periods of storage at room temperature or at temperatures ranging from 2°C to 8°C (e.g., including 5°C). As used herein, room temperature is generally a temperature ranging from 22°C to 25°C. Suitably, the pharmaceutical formulations are stable after storage at temperatures ranging from 2°C to 8°C (e.g., including 5°C) for at least 1 month, at least 3 months, or at least 6 months. As used herein, the term "stable" (or "stability") during the storage period is used to indicate that the formulation resists aggregation, degradation, formation of half antibodies, and / or fragmentation. The stability of monoclonal antibodies can be assessed by the degree of aggregation, degradation, half-antibody formation, or fragmentation as measured by high performance size exclusion chromatography (HPSEC), static light scattering (SLS), Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD), urea unfolding technique, intrinsic tryptophan fluorescence, differential scanning calorimetry, and / or ANS binding techniques, in comparison to a standard.

[0106] When intended for parenteral administration, the therapeutic composition for use may be provided in the form of a pyrogen-free parenterally acceptable aqueous solution containing an anti-RSV antibody or its antigen-binding fragment in a pharma- ceutically acceptable vehicle. In some embodiments, a vehicle particularly suitable for parenteral injection is sterile distilled water in which the antibody is formulated as a sterile isotonic solution and properly preserved. Additionally or alternatively, formulations suitable for parenteral administration may include a sterile aqueous preparation of an anti-RSV antibody or its antigen-binding fragment, or a dispersion of a sterile powder of an anti-RSV antibody or its antigen-binding fragment, which may be isotonic with the blood of the recipient. Isotonic agents that may be included in the liquid preparation include sugars, buffers, and sodium chloride. Solutions of an anti-RSV antibody or its antigen-binding fragment may be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions of anti-RSV antibodies or antigen-binding fragments thereof carriers can be prepared, for example, in water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, glycerol esters, and mixtures thereof. In some embodiments, the final dosage form can be sterile, fluid, and stable under the conditions of manufacture and storage. The required fluidity can be obtained, for example, by the use of liposomes, by the use of appropriate particle size in the case of dispersions, or by the use of surfactants. Sterilization of liquid preparations can be achieved by a method suitable for preserving the biological activity of the anti-RSV antibodies or antigen-binding fragments thereof, for example, by filter sterilization. Methods for preparing powders include vacuum drying and lyophilization of sterile injection solutions. Subsequent microbial contamination can be prevented by various antimicrobial agents, for example, antibacterial, antiviral, and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. Absorption of anti-RSV antibodies or antigen-binding fragments thereof over a prolonged period can be achieved by including delaying agents, for example, aluminum monostearate and gelatin.

[0107] In certain embodiments, the composition may comprise a formulation of an anti-RSV antibody or an antigen-binding fragment thereof with an agent such as an injectable microsphere, a biodegradable particle, a polymeric compound (such as polylactic acid or polyglycolic acid), a bead, or a liposome, which may provide a controlled or sustained release product that may be delivered by depot injection. In certain embodiments, hyaluronic acid may also be used, which has the effect of promoting duration in the circulation. In certain embodiments, an implantable drug delivery device may be used to introduce the antibody.

[0108] In some embodiments, the composition can be conveniently provided in unit dosage form.For example, exemplary pharmaceutical unit dosages include 50mg nirsevimab, 100mg nirsevimab, or 200mg nirsevimab.Such unit dosages can be prepared by methods well known in the art of pharmacy.In some embodiments, the unit dosage is suitable for parenteral administration, including intramuscular administration.

[0109] Exemplary Method Embodiments - Patient Age and Weight 1. A method for treating or preventing a RSV infection in a patient in need thereof, comprising: Determining the patient's age; administering a fixed dose of 200 milligrams (mg) of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient in the second year of life; To determine the patient's weight relative to the patient's first year of life; and Administering a fixed dose of 100 mg of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient having a body weight of at least 5 kilograms (kg). Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a neutralization assay for RSV A, or an IC50 of 3.0 ng / ml or less in a neutralization assay for RSV B9320, or both.

[0110] 2. The method of embodiment 1, wherein the anti-RSV monoclonal antibody or antigen-binding fragment of an anti-RSV monoclonal antibody comprises a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:1, and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.

[0111] 3. The method of embodiment 1 or 2, wherein the anti-RSV monoclonal antibody or antigen-binding fragment of an anti-RSV monoclonal antibody comprises a sequence comprising SEQ ID NO:1 and / or SEQ ID NO:2.

[0112] 4. The anti-RSV monoclonal antibody or the antigen-binding fragment of the anti-RSV monoclonal antibody is a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QASQDIVNYLN (SEQ ID NO:3); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence VASNLET (SEQ ID NO:4); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QQYDNLPLT (SEQ ID NO:5); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence DYIIN (SEQ ID NO:6); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence GIIPVLGTVHYGPKFQG (SEQ ID NO: 7); and / or A sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence ETALVVSETYLPHYFDN (SEQ ID NO:8). The method according to any one of embodiments 1 to 3, comprising:

[0113] 5. The method of any one of embodiments 1-4, wherein the anti-RSV monoclonal antibody or antigen-binding fragment of the anti-RSV monoclonal antibody comprises QASQDIVNYLN (SEQ ID NO: 3), VASNLET (SEQ ID NO: 4), QQYDNLPLT (SEQ ID NO: 5), DYIIN (SEQ ID NO: 6), GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and / or ETALVVSETYLPHYFDN (SEQ ID NO: 8).

[0114] 6. The method of any one of embodiments 1 to 5, wherein the anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody comprises QASQDIVNYLN (SEQ ID NO: 3), VASNLET (SEQ ID NO: 4), QQYDNLPLT (SEQ ID NO: 5), DYIIN (SEQ ID NO: 6), GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and ETALVVSETYLPHYFDN (SEQ ID NO: 8).

[0115] 7. The method of any one of embodiments 1 to 6, wherein the anti-RSV monoclonal antibody comprises a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:9, and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:10.

[0116] 8. The method of any one of embodiments 1 to 7, wherein the anti-RSV monoclonal antibody comprises nirsevimab, or the antigen-binding fragment of the anti-RSV monoclonal antibody comprises an antigen-binding fragment of nirsevimab.

[0117] 9. The method of any one of embodiments 1-8, wherein the patient having a body weight of at least 5 kg has a body weight of up to 10 kg, up to 15 kg, or up to 20 kg.

[0118] 10. The method of any one of embodiments 1-9, wherein the patient in the first year of life is at least 1 month, at least 3 months, or at least 6 months of age.

[0119] 11. The method of any one of embodiments 1-10, wherein the patient in the second year of life is at least 1 year and up to 2 years of age.

[0120] 12. The method of any one of embodiments 1-11, wherein the patient has a gestational age of at least 29 weeks.

[0121] 13. Patients had an AUC of >13.4 day·mg / mL 0-∞ The method according to any one of embodiments 1 to 12, wherein

[0122] 14. The method of any one of embodiments 1-13, comprising administering the dose at the beginning of a RSV season.

[0123] 15. The method of any one of embodiments 1-14, comprising administering the dose intramuscularly.

[0124] 16. The method of any one of embodiments 1-15, wherein the patient exhibits Down's syndrome, immunodeficiency, congenital lung disease, or congenital heart disease, or a combination thereof.

[0125] 17. The method of any one of embodiments 1-16, wherein the patient exhibits congenital pulmonary disease, or congenital heart disease, or both.

[0126] 18. The method of any one of embodiments 1 to 17, comprising administering an anti-RSV monoclonal antibody or an antigen-binding fragment thereof in a composition comprising at least one of an ionic excipient, a buffer, a sugar, and a surfactant.

[0127] 19. The method of embodiment 28, wherein the ionic excipient comprises L-arginine hydrochloride at a concentration of 80 mM.

[0128] 20. The pharmaceutical unit dose of embodiment 18 or 19, wherein the buffer comprises 30 mM L-histidine / L-histidine hydrochloride, the sugar comprises 120 mM sucrose, and the surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v).

[0129] 21. The method of any one of embodiments 18 to 20, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof in the composition is stable for at least 3 months at 2°C to 8°C as measured by high performance size exclusion chromatography (HPSEC).

[0130] 22. The method of any one of embodiments 18 to 21, wherein the composition has a pH in the range of 5.5 to 6.5.

[0131] 23. The method of any one of embodiments 18 to 22, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof is present in the composition at a concentration of 100 mg / mL.

[0132] Exemplary Method Embodiments - Patient Age or Weight 1. A method of treating or preventing a RSV infection in a patient in need thereof, comprising administering to a patient having a body weight of at least 5 kilograms (kg) a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in a RSV B9320 neutralization assay, or both.

[0133] 2. A method for treating or preventing a RSV infection in a patient in need thereof, comprising: Determining the patient's weight; Administering to a patient weighing at least 5 kilograms (kg) a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in a RSV B9320 neutralization assay, or both: Administering a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient weighing up to 5 kg, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a neutralization assay for RSV A, or an IC50 of 3.0 ng / ml or less in a neutralization assay for RSV B9320, or both. The method includes:

[0134] 3. The method of embodiment 1 or 2, wherein the patient having a body weight of at least 5 kg has a body weight of up to 10 kg, up to 15 kg, or up to 20 kg.

[0135] 4. A method for treating or preventing a RSV infection in a patient in need thereof, comprising: Determining the patient's age; and Administering to a patient 3 months of age or older a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a neutralization assay for RSV A, or an IC50 of 3.0 ng / ml or less in a neutralization assay for RSV B9320, or both. The method includes:

[0136] 5. The method of embodiment 4, wherein the patient is 6 months of age or older.

[0137] 6. The method of embodiment 4 or 5, wherein the patient is up to 2 years of age.

[0138] 7. A method for treating or preventing a RSV infection in a patient in need thereof, comprising: Determining the patient's age; administering a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to patients 3 months of age or older; A fixed dose of 100 mg of anti-RSV monoclonal antibody or antigen-binding fragment thereof should be administered to patients up to 3 months of age. Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a neutralization assay for RSV A, or an IC50 of 3.0 ng / ml or less in a neutralization assay for RSV B9320, or both.

[0139] 8. The method of embodiment 7, wherein the patient 3 months of age or older is up to 2 years of age.

[0140] 9. A method for treating or preventing a RSV infection in a patient in need thereof, comprising: Determining the patient's age; administering a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to patients 6 months of age or older; A fixed dose of 100 mg of anti-RSV monoclonal antibody or antigen-binding fragment thereof should be administered to patients up to 6 months of age. Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a neutralization assay for RSV A, or an IC50 of 3.0 ng / ml or less in a neutralization assay for RSV B9320, or both.

[0141] 10. The method of embodiment 9, wherein the patient is 6 months of age or older, up to 2 years of age.

[0142] 11. The method of any one of embodiments 1-10, wherein the patient has a gestational age of at least 29 weeks.

[0143] 12. Patients had an AUC of >13.4 day·mg / mL 0-∞ The method according to any one of embodiments 1 to 11, wherein

[0144] 13. The method of any one of embodiments 1-12, comprising administering the dose at the beginning of a RSV season.

[0145] 14. The method of any one of embodiments 1-13, comprising administering the dose intramuscularly.

[0146] 15. The method of any one of embodiments 1-14, wherein the patient exhibits Down's syndrome, immunodeficiency, congenital lung disease, or congenital heart disease, or a combination thereof.

[0147] 16. The method of any one of embodiments 1-15, wherein the patient exhibits congenital pulmonary disease, or congenital heart disease, or both.

[0148] 17. The method of any one of embodiments 1 to 16, comprising administering an anti-RSV monoclonal antibody or an antigen-binding fragment thereof in a composition comprising at least one of an ionic excipient, a buffer, a sugar, and a surfactant.

[0149] 18. The method of embodiment 17, wherein the ionic excipient comprises L-arginine hydrochloride at a concentration of 80 mM.

[0150] 19. The method of embodiment 17 or embodiment 18, wherein the buffer comprises 30 mM L-histidine / L-histidine hydrochloride, the sugar comprises 120 mM sucrose, and / or the surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v).

[0151] 20. The method of any one of embodiments 18-19, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof in the composition is stable for at least 3 months at 2°C to 8°C as measured by high performance size exclusion chromatography (HPSEC).

[0152] 21. The method of any one of embodiments 18 to 20, wherein the composition has a pH in the range of 5.5 to 6.5.

[0153] 22. The method of any one of embodiments 18 to 21, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof is present in the composition at a concentration of 100 mg / mL.

[0154] 23. The method of any one of embodiments 1 to 22, wherein the anti-RSV monoclonal antibody or antigen-binding fragment of the anti-RSV monoclonal antibody comprises a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:1, and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.

[0155] 24. The method of any one of embodiments 1 to 23, wherein the anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody comprises a sequence comprising SEQ ID NO:1 and / or SEQ ID NO:2.

[0156] 25. The anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody is a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QASQDIVNYLN (SEQ ID NO:3); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence VASNLET (SEQ ID NO:4); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QQYDNLPLT (SEQ ID NO:5); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence DYIIN (SEQ ID NO:6); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence GIIPVLGTVHYGPKFQG (SEQ ID NO: 7); and / or A sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence ETALVVSETYLPHYFDN (SEQ ID NO:8). 25. The method according to any one of embodiments 1 to 24, comprising:

[0157] 26. The method of any one of embodiments 1 to 25, wherein the anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody comprises QASQDIVNYLN (SEQ ID NO: 3), VASNLET (SEQ ID NO: 4), QQYDNLPLT (SEQ ID NO: 5), DYIIN (SEQ ID NO: 6), GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and / or ETALVVSETYLPHYFDN (SEQ ID NO: 8).

[0158] 27. The method of any one of embodiments 1 to 26, wherein the anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody comprises QASQDIVNYLN (SEQ ID NO: 3), VASNLET (SEQ ID NO: 4), QQYDNLPLT (SEQ ID NO: 5), DYIIN (SEQ ID NO: 6), GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and ETALVVSETYLPHYFDN (SEQ ID NO: 8).

[0159] 28. The method according to any one of embodiments 1 to 27, wherein the anti-RSV monoclonal antibody comprises a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:9, and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:10.

[0160] 29. The method of any one of embodiments 1 to 28, wherein the anti-RSV monoclonal antibody comprises nirsevimab, or the antigen-binding fragment of the anti-RSV monoclonal antibody comprises an antigen-binding fragment of nirsevimab.

[0161] Exemplary Method Embodiments - RSV Season and Weight of Patients 1. A method for treating or preventing a RSV infection in a patient in need thereof, comprising: To determine whether the patient is experiencing a first or second RSV season; administering a fixed dose of 200 milligrams (mg) of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient experiencing a second RSV pandemic; Determining the patient's weight relative to the patient experiencing their first RSV episode; and Administering a fixed dose of 100 mg of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient having a body weight of at least 5 kilograms (kg). Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a neutralization assay for RSV A, or an IC50 of 3.0 ng / ml or less in a neutralization assay for RSV B9320, or both.

[0162] 2. The method of embodiment 1, wherein the anti-RSV monoclonal antibody or antigen-binding fragment of an anti-RSV monoclonal antibody comprises a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:1, and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.

[0163] 3. The method of embodiment 1 or 2, wherein the anti-RSV monoclonal antibody or antigen-binding fragment of an anti-RSV monoclonal antibody comprises a sequence comprising SEQ ID NO:1 and / or SEQ ID NO:2.

[0164] 4. The anti-RSV monoclonal antibody or the antigen-binding fragment of the anti-RSV monoclonal antibody is a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QASQDIVNYLN (SEQ ID NO:3); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence VASNLET (SEQ ID NO:4); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QQYDNLPLT (SEQ ID NO:5); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence DYIIN (SEQ ID NO:6); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence GIIPVLGTVHYGPKFQG (SEQ ID NO: 7); and / or A sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence ETALVVSETYLPHYFDN (SEQ ID NO:8). The method according to any one of embodiments 1 to 3, comprising:

[0165] 5. The method of any one of embodiments 1-4, wherein the anti-RSV monoclonal antibody or antigen-binding fragment of the anti-RSV monoclonal antibody comprises QASQDIVNYLN (SEQ ID NO: 3), VASNLET (SEQ ID NO: 4), QQYDNLPLT (SEQ ID NO: 5), DYIIN (SEQ ID NO: 6), GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and / or ETALVVSETYLPHYFDN (SEQ ID NO: 8).

[0166] 6. The method of any one of embodiments 1 to 5, wherein the anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody comprises QASQDIVNYLN (SEQ ID NO: 3), VASNLET (SEQ ID NO: 4), QQYDNLPLT (SEQ ID NO: 5), DYIIN (SEQ ID NO: 6), GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and ETALVVSETYLPHYFDN (SEQ ID NO: 8).

[0167] 7. The method of any one of embodiments 1 to 6, wherein the anti-RSV monoclonal antibody comprises a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:9, and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:10.

[0168] 8. The method of any one of embodiments 1 to 7, wherein the anti-RSV monoclonal antibody comprises nirsevimab, or the antigen-binding fragment of the anti-RSV monoclonal antibody comprises an antigen-binding fragment of nirsevimab.

[0169] 9. The method of any one of embodiments 1-8, wherein the patient having a body weight of at least 5 kg has a body weight of up to 10 kg, up to 15 kg, or up to 20 kg.

[0170] 10. The method of any one of embodiments 1-9, wherein the patient experiencing a first RSV epidemic is at least 1 month, at least 3 months, or at least 6 months of age.

[0171] 11. The method of any one of embodiments 1-10, wherein the patient experiencing a second RSV season is at least 6 months and up to 2 years old.

[0172] 12. The method of any one of embodiments 1-11, wherein the patient has a gestational age of at least 29 weeks.

[0173] 13. Patients had an AUC of >13.4 day·mg / mL 0-∞ The method according to any one of embodiments 1 to 12, wherein

[0174] 14. The method of any one of embodiments 1-13, comprising administering the dose at the beginning of a RSV season.

[0175] 15. The method of any one of embodiments 1-14, comprising administering the dose intramuscularly.

[0176] 16. The method of any one of embodiments 1-15, wherein the patient exhibits Down's syndrome, immunodeficiency, congenital lung disease, or congenital heart disease, or a combination thereof.

[0177] 17. The method of any one of embodiments 1-16, wherein the patient exhibits congenital pulmonary disease, or congenital heart disease, or both.

[0178] 18. The method of any one of embodiments 1 to 17, comprising administering an anti-RSV monoclonal antibody or an antigen-binding fragment thereof in a composition comprising at least one of an ionic excipient, a buffer, a sugar, and a surfactant.

[0179] 19. The method of embodiment 28, wherein the ionic excipient comprises L-arginine hydrochloride at a concentration of 80 mM.

[0180] 20. The pharmaceutical unit dose of embodiment 18 or 19, wherein the buffer comprises 30 mM L-histidine / L-histidine hydrochloride, the sugar comprises 120 mM sucrose, and the surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v).

[0181] 21. The method of any one of embodiments 18 to 20, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof in the composition is stable for at least 3 months at 2°C to 8°C as measured by high performance size exclusion chromatography (HPSEC).

[0182] 22. The method of any one of embodiments 18 to 21, wherein the composition has a pH in the range of 5.5 to 6.5.

[0183] 23. The method of any one of embodiments 18 to 22, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof is present in the composition at a concentration of 100 mg / mL.

[0184] Exemplary Method Embodiments—RSV Phase of Patient 1. A method for treating or preventing a RSV infection in a patient in need thereof, comprising: To determine whether the patient is experiencing a first or second RSV season; Administering a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient experiencing a second RSV pandemic, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a neutralization assay for RSV A, or an IC50 of 3.0 ng / ml or less in a neutralization assay for RSV B9320, or both. The method includes:

[0185] 2. The method of embodiment 1, wherein the patient is 3 months of age or older.

[0186] 3. The method of embodiment 1, wherein the patient is 6 months of age or older.

[0187] 4. The method of any one of embodiments 1-3, wherein the patient is up to 2 years of age.

[0188] 5. A method for treating or preventing a RSV infection in a patient in need thereof, comprising: To determine whether the patient is experiencing a first or second RSV season; administering to a patient a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof, wherein the patient is experiencing a second RSV pandemic; administering to a patient a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof, wherein the patient has experienced a first RSV epidemic. Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in a neutralization assay for RSV A, or an IC50 of 3.0 ng / ml or less in a neutralization assay for RSV B9320, or both.

[0189] 8. The method of embodiment 7, wherein the patient is up to 2 years of age.

[0190] 9. The method of any one of embodiments 1-8, wherein the patient weighs at least 5 kg.

[0191] 10. The method of any one of embodiments 1-9, wherein the patient has a gestational age of at least 29 weeks.

[0192] 11. Patients had an AUC of >13.4 day·mg / mL 0-∞ The method according to any one of embodiments 1 to 10, wherein

[0193] 12. The method of any one of embodiments 1-11, comprising administering the dose at the beginning of a RSV season.

[0194] 13. The method of any one of embodiments 1-12, comprising administering the dose intramuscularly.

[0195] 14. The method of any one of embodiments 1-13, wherein the patient exhibits Down's syndrome, immunodeficiency, congenital lung disease, or congenital heart disease, or a combination thereof.

[0196] 15. The method of any one of embodiments 1-14, wherein the patient exhibits congenital pulmonary disease, or congenital heart disease, or both.

[0197] 16. The method of any one of embodiments 1 to 15, comprising administering an anti-RSV monoclonal antibody or an antigen-binding fragment thereof in a composition comprising at least one of an ionic excipient, a buffer, a sugar, and a surfactant.

[0198] 17. The method of embodiment 16, wherein the ionic excipient comprises L-arginine hydrochloride at a concentration of 80 mM.

[0199] 18. The method of embodiment 16 or embodiment 17, wherein the buffer comprises 30 mM L-histidine / L-histidine hydrochloride, the sugar comprises 120 mM sucrose, and / or the surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v).

[0200] 19. The method of any one of embodiments 17 to 19, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof in the composition is stable for at least 3 months at 2°C to 8°C as measured by high performance size exclusion chromatography (HPSEC).

[0201] 20. The method of any one of embodiments 17 to 21, wherein the composition has a pH in the range of 5.5 to 6.5.

[0202] 21. The method of any one of embodiments 17 to 21, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof is present in the composition at a concentration of 100 mg / mL.

[0203] 22. The method of any one of embodiments 1 to 21, wherein the anti-RSV monoclonal antibody or antigen-binding fragment of the anti-RSV monoclonal antibody comprises a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:1, and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.

[0204] 23. The method of any one of embodiments 1 to 22, wherein the anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody comprises a sequence comprising SEQ ID NO:1 and / or SEQ ID NO:2.

[0205] 24. The anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody is a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QASQDIVNYLN (SEQ ID NO:3); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence VASNLET (SEQ ID NO:4); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence QQYDNLPLT (SEQ ID NO:5); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence DYIIN (SEQ ID NO:6); a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence GIIPVLGTVHYGPKFQG (SEQ ID NO: 7); and / or A sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence ETALVVSETYLPHYFDN (SEQ ID NO:8). 24. The method according to any one of embodiments 1 to 23, comprising:

[0206] 25. The method of any one of embodiments 1 to 24, wherein the anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody comprises QASQDIVNYLN (SEQ ID NO: 3), VASNLET (SEQ ID NO: 4), QQYDNLPLT (SEQ ID NO: 5), DYIIN (SEQ ID NO: 6), GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and / or ETALVVSETYLPHYFDN (SEQ ID NO: 8).

[0207] 26. The method of any one of embodiments 1 to 25, wherein the anti-RSV monoclonal antibody or an antigen-binding fragment of an anti-RSV monoclonal antibody comprises QASQDIVNYLN (SEQ ID NO: 3), VASNLET (SEQ ID NO: 4), QQYDNLPLT (SEQ ID NO: 5), DYIIN (SEQ ID NO: 6), GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and ETALVVSETYLPHYFDN (SEQ ID NO: 8).

[0208] 27. The method of any one of embodiments 1 to 26, wherein the anti-RSV monoclonal antibody comprises a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:9, and / or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO:10.

[0209] 28. The method of any one of embodiments 1 to 27, wherein the anti-RSV monoclonal antibody comprises nirsevimab, or the antigen-binding fragment of the anti-RSV monoclonal antibody comprises an antigen-binding fragment of nirsevimab.

[0210] Exemplary Pharmaceutical Unit Dose Embodiments 1. A pharmaceutical unit dose comprising 100 mg of nirsevimab, said pharmaceutical unit dose being suitable for intramuscular administration.

[0211] 2. A pharmaceutical unit dose comprising 200 mg of nirsevimab, said pharmaceutical unit dose being suitable for intramuscular administration.

[0212] 3. The pharmaceutical unit dose of embodiment 1 or 2, comprising a composition comprising nirsevimab, wherein the composition further comprises at least one of an ionic excipient, a buffer, a sugar, and a surfactant.

[0213] 4. The pharmaceutical unit dose of embodiment 3, wherein the ionic excipient comprises L-arginine hydrochloride in a concentration of 80 mM.

[0214] 5. The pharmaceutical unit dose of embodiment 3 or embodiment 4, wherein the buffer comprises 30 mM L-histidine / L-histidine hydrochloride, the sugar comprises 120 mM sucrose, and the surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v).

[0215] 6. A pharmaceutical unit dose according to any one of embodiments 1 to 5, wherein the nirsevimab in the composition is stable at 2°C to 8°C for at least 3 months as measured by high performance size exclusion chromatography (HPSEC).

[0216] 7. The pharmaceutical unit dose according to any one of embodiments 3 to 6, wherein the composition has a pH in the range of 5.5 to 6.5.

[0217] 8. The pharmaceutical unit dose according to any one of embodiments 1 to 7, wherein nirsevimab is contained in a concentration of 100 mg / mL.

[0218] Exemplary Pharmaceutical Composition Embodiments 1. A pharmaceutical composition for the treatment or prevention of RSV infection, comprising 100 mg of nirsevimab, administered to a patient in the first year of life, wherein the patient has a body weight of at least 5 kg.

[0219] 2. The pharmaceutical composition of embodiment 1, which is administered when the patient enters their first RSV season.

[0220] 3. A pharmaceutical composition for the treatment or prevention of RSV infection, comprising 100 mg of nirsevimab, administered to a patient undergoing their first RSV epidemic.

[0221] 4. A pharmaceutical composition for the treatment or prevention of RSV infection, comprising 200 mg of nirsevimab, administered to a patient in the second year of life.

[0222] 5. The pharmaceutical composition of embodiment 3, wherein the patient is in the second RSV season.

[0223] 6. A pharmaceutical composition for the treatment or prevention of RSV infection, comprising 200 mg of nirsevimab, for administration to a patient undergoing a second RSV epidemic.

[0224] 7. The pharmaceutical composition according to any one of embodiments 1 to 6, wherein the patient exhibits congenital pulmonary disease, or congenital heart disease, or both.

[0225] 8. Patients had an AUC of >13.4 day·mg / mL 0-∞ The pharmaceutical composition according to any one of embodiments 1 to 7,

[0226] 9. The pharmaceutical composition according to any one of the preceding embodiments, having a pH in the range of 5.5 to 6.5.

[0227] 10. The pharmaceutical composition of any one of embodiments 1-9, further comprising at least one of an ionic excipient, a buffer, a sugar, and a surfactant.

[0228] 11. The pharmaceutical composition according to embodiment 10, comprising L-arginine hydrochloride in a concentration of 80 mM.

[0229] 12. The pharmaceutical composition according to embodiment 10 or 11, wherein the buffer comprises 30 mM L-histidine / L-histidine hydrochloride, the sugar comprises 120 mM sucrose, and the surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v).

[0230] 13. A pharmaceutical composition described in any one of embodiments 1 to 12, wherein nirsevimab in the pharmaceutical composition is stable at 2°C to 8°C for at least 3 months as measured by high performance size exclusion chromatography (HPSEC).

[0231] 14. The pharmaceutical unit dose according to any one of embodiments 1 to 13, wherein nirsevimab is contained in a concentration of 100 mg / mL.

[0232] The present invention is illustrated by the following examples, it being understood that the specific examples, materials, amounts, and procedures are to be interpreted broadly in accordance with the scope and spirit of the invention described herein. EXAMPLES

[0233] Example 1: Phase 2b study This example describes a Phase 2b study of nirsevimab. The primary objective of the study was to compare the efficacy of nirsevimab with placebo in reducing RSV-confirmed lower respiratory tract infections (LRTIs) requiring medical attention during the first 150 days after dosing (i.e., day 151; a typical 5-month RSV season period). Secondary efficacy objectives included comparing nirsevimab with placebo in reducing RSV-confirmed hospitalizations through day 151. Other objectives included comparing the safety and tolerability of nirsevimab with placebo, and evaluating the pharmacokinetic (PK) and anti-drug antibody (ADA) responses to nirsevimab.

[0234] The target serum concentration of 6.8 μg / mL in the Phase 2b study was based on an RSV challenge study in cotton rats, a model that has proven to be a reliable predictive model for target concentrations and is also used for dose selection of palivizumab (Synagis Summary of Product Characteristics, 2018). The selection of the 50 mg IM dose in the Phase 2b study was based on a population-PK model used to identify a dose that would maintain nirsevimab serum concentrations above 6.8 μg / mL throughout the RSV season. Nirsevimab met this exposure target (achieved by >95% of subjects) and the primary endpoint of the study by achieving a statistically significant relative risk reduction (RRR) of RSV-confirmed LRTIs requiring consultation compared to placebo and demonstrating safety.

[0235] The Phase 2b study was a randomized, double-blind, placebo-controlled study evaluating the safety, efficacy, PK, and immunogenicity of nirsevimab in healthy preterm infants born between 29 weeks 0 days and 34 weeks 6 days gestational age and entering their first RSV season (see Figure 3). Subjects were not eligible for RSV prophylaxis with palivizumab per Joint Committee on Vaccination and Immunisation, American Academy of Pediatrics, or other local or national guidelines and a placebo control arm was available. Subjects were randomized in a 2:1 ratio to receive a single IM dose of 50 mg nirsevimab or placebo. Randomization was stratified by hemisphere (North, South) and subject age at randomization (≤3 months, >3 months ≤6 months, >6 months). Subjects were followed for 360 days after dosing.

[0236] Subjects were monitored throughout the study for LRTIs. All subjects presenting for respiratory illness (hospitalization or outpatient care) were assessed for the development of LRTIs. Subjects presenting for primary respiratory hospitalization, respiratory deterioration during hospitalization, or outpatient care, including emergency department visits for respiratory illness, were assessed for RSV by diagnostic testing of respiratory secretions and clinical evaluation for the presence of LRTIs. Testing for RSV was performed centrally using a US FDA-approved and Conformite Europeenne marked in vitro diagnostic real-time RT-PCR assay (Lyra RSV+hMPV assay, Quidel Corporation, San Diego, CA; www.quidel.com). Diagnosis of RSV LRTI required a respiratory specimen positive for RSV by central RT-PCR assay.

[0237] Subject population Breakdown: As of the data cut-off (DCO) date for the primary analysis, all subjects were enrolled and a complete data set for all randomized subjects was available through day 151. Overall, 1,453 subjects (969, nirsevimab; 484, placebo) were randomized, and 1,447 received a single dose of nirsevimab (968) or placebo (479; Table 1). Two subjects randomized to the placebo group received nirsevimab in error; both subjects were included in the as-treated population of the nirsevimab group.

[0238] Most subjects completed efficacy follow-up through day 151 (948 [97.8%], nirsevimab; 474 [97.9%], placebo). As of the DCO date, 676 subjects (46.5%) had completed the study and 710 subjects (48.9%) were ongoing. The median number of days on study was 252 (range, 229-289).

[0239] Demographics. Demographic and baseline characteristics were comparable between the nirsevimab and placebo groups (Table 2). Overall, 52% of subjects were male, 72% were white, and 35% had a sibling enrolled in the study.

[0240] Effectiveness Primary endpoint: Incidence of RSV-confirmed LRTI requiring medical consultation Based on the primary analysis in the intent-to-treat (ITT) population, a single IM dose of nirsevimab 50 mg compared with placebo resulted in a relative risk reduction (RRR) of 70.2% (95% CI: 52.4%, 81.3%) in RSV-confirmed LRTI events requiring a medical visit by day 151 (p<0.0001; Table 3). Similar results were observed based on the same primary analysis model in the per-protocol population and the confirmatory Cochran-Mantel-Haenszel test in the ITT population (Table 3).

[0241] The incidence of all LRTIs (protocol-defined and non-protocol-defined) requiring a medical visit through day 151 was 19.7% in the nirsevimab group and 25.8% in the placebo group. As shown in Table 3, protocol-defined RSV-confirmed LRTIs were seen in 2.6% of subjects in the nirsevimab group and 9.5% of subjects in the placebo group. The incidence of non-RSV LRTIs (protocol-defined and non-protocol-defined) was generally similar between groups (Figure 4), suggesting that infections due to other viruses were not increased in the nirsevimab group.

[0242] The efficacy of nirsevimab through day 151 was confirmed by Kaplan-Meier analysis (p<0.0001; Figure 5).

[0243] Subgroup analyses showed consistent results for hemisphere, age at randomization, birth weight, weight on day 1, gestational age (GA), and siblings enrolled in the study, with no statistically significant interactions between each subgroup and treatment and relative risk reduction by day 151, favoring nirsevimab over placebo across all subgroups (Figure 6). Efficacy was seen in infants >5 kg, but was lower than that seen in lighter infants. Additional PK exposure-efficacy analyses showed that the 100 mg dose provided similar exposures for infants ≥5 kg, with the expected improved efficacy.

[0244] [Table 1]

[0245] [Table 2]

[0246] [Table 3]

[0247] Secondary endpoints - Incidence of hospitalization due to RSV LRTI Based on the primary analysis model in the intent-to-treat (ITT) population, a single IM dose of nirsevimab 50 mg resulted in a relative risk reduction (RRR) of 78.8% (95% CI: 52.3%, 90.6%) in the incidence of hospitalization due to RSV LRTI by day 151 compared with placebo (p=0.0002; Table 4). Similar results were observed based on the same primary analysis model in the per-protocol population and the confirmatory Cochran-Mantel-Haenszel test in the ITT population (Table 4).

[0248] Efficacy by RSV subtype Nirsevimab was active against RSV A and RSV B subtypes (Table 5). Overall and hospitalization-causing RSV LRTI rates through day 151 were similar for RSV A and RSV B subtypes. Incidence was significantly lower in the nirsevimab group than in the placebo group for both subtypes.

[0249] [Table 4]

[0250] [Table 5]

[0251] safety Summary of adverse events In the as-treated population, the incidence of treatment-emergent adverse events (TEAEs) in the nirsevimab group was generally similar to or less than that in the placebo group across all TEAE categories (Table 6). Overall, 83.7% of subjects in the nirsevimab group and 83.9% of subjects in the placebo group had at least one TEAE. TEAEs within 1 day of dosing occurred in 2.5% of subjects in both groups. Compared with the placebo group, the nirsevimab group had a lower incidence of TEAEs occurring within 7 days of dosing (15.2% vs. 12.5%, respectively), TEAEs of grade 3 or greater severity (12.3% vs. 7.4%, respectively), or TESAEs (16.7% vs. 10.4%, respectively).

[0252] During the study period up to day 361, at the time of the DCO for the primary analysis, five deaths were reported, including two (0.2%) in the nirsevimab group and three (0.6%) in the placebo group. One additional death occurred in the placebo group on day 367. None of these deaths were related to study treatment by the investigator.

[0253] Overall, the incidence of treatment-related AEs (2.3% nirsevimab vs. 2.1% placebo); adverse events of special interest (AESIs) including hypersensitivity, immune complex disorders, and thrombocytopenia (0.5% nirsevimab vs. 0.6% placebo); and NOCDs (0.3% nirsevimab vs. 0.8% placebo) was low and generally similar between placebo and nirsevimab groups. Skin reactions were collected as TEAEs related to the skin and subcutaneous tissues (including diaper rash), but excluded some clearly diagnosable skin reactions such as impetigo, chickenpox, and scabies. The proportion of subjects reporting skin reactions was similar in both treatment groups (28.2% nirsevimab vs. 26.5% placebo).

[0254] Adverse events The TEAE profiles were generally similar between the nirsevimab and placebo groups (Table 7). Upper respiratory tract infections (URTIs) were the most common TEAE in both groups (nirsevimab 38.5%, placebo 32.6%). Similarly, the proportion of subjects with TEAEs overall or within 1 or 7 days of dosing in each age group (≤3 months, >3 months <6 months, or >6 months) was comparable between the nirsevimab and placebo groups (Tables 6, 8).

[0255] The proportion of subjects who experienced investigator-reported treatment-related TEAEs was generally similar between the nirsevimab and placebo groups overall and in the three age groups (Tables 6, 8). No subjects reported a score of 3 or more for any treatment-related event.

[0256] Serious Adverse Events In general, the incidence of treatment-emergent serious adverse events (TESAEs) tended to be lower in the nirsevimab groups than in the placebo groups (overall: nirsevimab 10.4% vs. placebo 16.7%; (Table 9). The most common TESAEs based on the nirsevimab group were bronchiolitis (nirsevimab 2.1%, placebo 4.2%), lower respiratory tract infection (nirsevimab 1.4%, placebo 2.7%), pneumonia (nirsevimab 1.4%, placebo 2.1%), and bronchitis (nirsevimab 1.2%, placebo 2.3%). No TESAEs were considered related to study treatment by the investigators (Table 6).

[0257] Adverse events of particular interest Five AESIs (0.5%) were reported in the nirsevimab group and three (0.6%) in the placebo group (Table 10). All events were grade 1 in severity. The TEAE of petechiae reported as an AESI was 1 day and was reported by the site investigator based on parental reporting. There was no laboratory evaluation of petechiae.

[0258] [Table 6]

[0259] [Table 7]

[0260] [Table 8]

[0261] [Table 9]

[0262] [Table 10]

[0263] Pharmacokinetics Following a single IM fixed dose of 50 mg nirsevimab, >95% of measurable serum nirsevimab concentrations through Day 151 were within the preclinical EC 90 This exceeded the target value of 6.8 μg / mL (Table 11).

[0264] Noncompartmental analysis of 26 infants who had minimal planned PK sampling plans but sufficient additional PK samples available from unscheduled visits demonstrated that AUC 0-∞ and apparent t1 / 2 could be estimated. Overall, AUC 0-∞ and the median estimated apparent t1 / 2 were 5.3 days·mg / mL (range 3.2–10.2 days·mg / mL) and 56.5 days (range 46.8–81.1 days), respectively.

[0265] [Table 11]

[0266] Anti-drug antibodies Overall, the rates and titers of anti-drug antibodies (ADA) were low, with no impact on PK or safety in ADA-positive subjects. Among subjects with serum samples available for testing, ADA was detected after baseline in 4.3% (40 / 921) of subjects in the nirsevimab group and 2.8% (13 / 466) of subjects in the placebo group at days 91 (1.2% nirsevimab, 0.9% placebo), 151 (2.0% nirsevimab, 1.4% placebo), and 361 (3.5% nirsevimab, 1.5% placebo). ADA titers ranged from 1:50 to 1:3,200 in the nirsevimab group and 1:50 to 1:200 in the placebo group.

[0267] Among nirsevimab subjects who became ADA-positive after baseline, ADAs directed against the YTE domain were present in 4 / 17 (23.5%) at day 151 and 10 / 15 (66.7%) at day 361. Two nirsevimab subjects had NAbs at day 361. Among placebo subjects who became ADA-positive after baseline, ADAs directed against the YTE domain were present in 3 / 3 at day 361; one had an NAb at day 361.

[0268] Nirsevimab resistance A total of 103 RSV-positive serum samples (from 40 nirsevimab-treated and 63 placebo-treated subjects; measured by Lyra RSV+hMPV real-time RT-PCR) were subjected to F gene Sanger sequencing to obtain full-length F gene sequences and analyzed with 53 RSV A and 50 RSV B sequences. Of these samples, 84 samples (from 29 nirsevimab-treated and 55 placebo-treated subjects) showed LRTI-specific findings (protocol-defined and non-protocol-defined) occurring during the initial epidemic (up to day 151). The remaining 19 sequences were isolated from subjects with URTIs (4 nirsevimab-treated, 3 placebo-treated), from subjects with LRTIs outside the 150-day time window (6 nirsevimab-treated, 2 placebo-treated), or from samples accidentally collected from multiple samples taken from the same subject during a single clinical episode that resulted in identical sequences (1 nirsevimab-treated, 3 placebo-treated). All F gene sequences were aligned and compared to the consensus sequence to identify potential amino acid mutations within the nirsevimab binding site (Table 12). Amino acid mutations K209R in RSV A and I206M+Q209R in RSV B in the nirsevimab binding site have been seen in prior studies of naive subjects and do not alter susceptibility to nirsevimab (Zhu et al, 2018 J Infect Dis. 218(4):572-580). Of the other two viruses that identified mutations in the nirsevimab binding site compared to the consensus, one encoded an N208S change in the F sequence, and the other isolate encoded changes at I64I / T+K68K / E+I206M+Q209R. The N208S change was previously identified in preclinical studies, and such a mutation in RSV B9320 results in a substantial change in susceptibility to nirsevimab. The combination of I64T+K68E+I206M+Q209R has not been observed in nature before, and recombinant RSV B9320 viruses engineered to carry these four mutations in the binding site showed altered susceptibility to nirsevimab. These two viruses containing resistance-associated mutations were identified in nasal specimens from nirsevimab-treated subjects hospitalized with LRTI.

[0269] [Table 12]

[0270] Example 2 Results from a Phase 2b study (see Example 1) demonstrated clinical efficacy of a single 50 mg IM dose of nirsevimab in preterm infants with gestational ages ranging from 29 to <35 weeks. Further analysis revealed that the fixed 50 mg dose evaluated in Example 1 resulted in a wide distribution of weight-normalized doses among the 968 infants who received nirsevimab, with a mean of 13.2 mg / kg (interquartile range [IQR], 8.33, 17.2 mg / kg) and 83 unique dose levels. This wide distribution of dose levels facilitated exposure-response analysis without considering multiple fixed doses in this population or individual doses based on weight, which could be potentially error-prone.

[0271] Population PK and exposure-response analyses were performed to: 1) identify relevant sources of intersubject variability in nirsevimab PK in adults and preterm infants; 2) examine the relationship between nirsevimab serum exposure and the primary efficacy outcome in consulted RSV-confirmed LRTI; and 3) perform dose optimization analyses to identify the clinical dose for future studies.

[0272] Test Data The population pharmacokinetic (popPK) dataset included clinical serum pharmacokinetic (PK) data from a phase 1 study in healthy adult volunteers (Griffin et al. 2017, Antimicrob Agents Chemother. 61(3), pii:e01714-16), a phase 1b / 2a study in healthy preterm infants with gestational age (GA) 32-35 weeks (Domachowske et al. Pediatr Infect Dis J. 2018;37(9):886-892), and a phase 2b study in healthy preterm infants with GA 29-35 weeks (Example 1). The exposure-response analysis dataset consisted of efficacy data from phase 2b and included empirical Bayes estimates from the popPK analysis (based on 1530 concentrations from 102 adults and a total of 2348 concentrations from 988 infants, including 43 and 134 concentrations below the limit of quantification, respectively).

[0273] Sample and data collection Details of the study design, dose, and population are outlined in Table 13.

[0274] [Table 13]

[0275] biological analysis method Nirsevimab concentrations in human serum samples were measured using a validated fluorescent ELISA method with a lower limit of quantification (LLOQ) value of 0.5 μg / mL. An electrochemiluminescence (ECL), liquid-phase, bridging immunoassay was used for detection, confirmation, and titration of anti-drug antibodies (ADA) in human serum.

[0276] Dataset preparation and processing PK and clinical efficacy data were assembled using SAS (SAS Institute Inc., Cary, NC, USA) and R (R Foundation for Statistical Computing, Vienna, Austria) software. SAS programs were implemented using data definition tables and specifications, after which validation and quality control were performed to ensure data consistency, reliability, and accuracy for all original or derived variables. PopPK data included demographic-related parameters such as baseline and time-varying age, weight, sex, ethnicity, race, gestational age, and geographic location. Derived parameters included postmenstrual age estimated as the sum of gestational age and chronological age. Imputation methods for missing baseline or postbaseline weight have been previously described (Robbie et al. in the References section, "Robbie et al. 2013 Antimicrob Agents Chemother. 57:6147-53").

[0277] The exposure-response dataset includes baseline clearance, prediction AUC inf , AUC 0-inf , AUC 0-150 A data frame containing estimated individual PK parameters output from the NONMEM program (Icon plc, Dublin, Ireland) such as was assembled by merging with the demographic data set for the Phase 2b study using R software.

[0278] Data Processing Serum PK data from all subjects treated with nirsevimab in the phase 1 and phase 1b / 2a studies were included in the popPK analysis. In phase 2b, 51 infants were excluded because post-treatment PK could not be quantified. As a result, only the remaining 917 infants treated with nirsevimab and 479 infants in the placebo group were included in the exposure-response analysis.

[0279] Population Pharmacokinetic and Exposure-Response Modeling Strategies Population Pharmacokinetics: Structural and Statistical Models A two-compartment model with first-order absorption, distributional clearance, and linear central elimination adequately characterized the PK data from the two studies. Figures 7 and 8 show a schematic of the popPK analysis workflow and the structural model, respectively.

[0280] Between-subject variance (BSV) terms were estimated for total body clearance, central volume of distribution, and absorption rate. In the covariate models for the two studies, we followed the allometric scaling of body weight for clearance and volume and included only the effects of body weight and maturation on clearance. Of note, the ETA distributions for clearance and absorption deviated significantly from the normality assumption for these parameters. Therefore, we used a Box-Cox transformation to address this issue. This facilitated the simultaneous fitting of densely sampled adult data and sparse PK data in infants. The strategy for the current study involved using base estimates from a previous popPK model as the initial structural model for the analysis. The effects of allometric scaling body weight and maturation on clearance were evaluated. Additional covariates such as anti-drug antibodies for clearance and ethnicity for volume of distribution were also included in the covariate analysis. A full-model approach followed by univariate reduction methods was used for final covariate selection. To maximize efficiency during parameter estimation, PK parameters were mu-referenced and an importance sampling expectation-maximization estimation algorithm was used within NONMEM. Details regarding the modeling approach and workflow are outlined in Figure 7.

[0281] Model evaluation Standard diagnostic and goodness-of-fit (GOF) plots were used to assess the validity of the popPK models. The validity and precision of the PK parameter estimates were also used as criteria for model selection. Nonparametric bootstrapping of 500 sampled data sets with replacement stratified by population (e.g., adults vs. infants) was performed using Perl speaks NONMEM (PsN) (Lindbom et al., 2004 Comput Methods Programs Biomed. 75(2):85-94) to assess model robustness and calculate confidence intervals for parameter estimates. Simulation-based visual predictive checks were performed using the final covariate model parameters to further assess model validity. Similar methods were employed for the qualification and evaluation of exposure-response models.

[0282] Exposure assessment criteria and exposure-response analysis The final covariate popPK model was used to calculate empirical Bayes estimates of PK parameters to perform exposure-response (ER) analyses.A semiparametric exploratory quartile analysis was performed for the primary efficacy outcome in phase 2b (PCR-confirmed RSV-positive referral lower respiratory tract infection (MALRTI)) by fitting a Cox proportional hazards model to the ER dataset using R software.

[0283] Specifically, the incidence of a first MALRTI event was characterized using the time-to-event method. The survival function is defined as the probability that an individual in the study experiences an event at a time greater than 0. The probability of not developing a MALRTI was estimated according to the relationship shown in Equation 1 below:

number

[0284] The probability density function, which in this case is also the probability of MALRTI at any time point t, was estimated as the product of the instantaneous hazard and the survival probability at time point t, as shown in Equation 2.

number

[0285] Probability density functions were determined for infants who developed MALRTI at time=t, whereas survival functions were used for infants for whom efficacy data were right-censored, i.e., infants whose MALRTI development was not known over the time of interest (150 days after dosing) or who discontinued the study or withdrew consent before the censoring time. In particular, Schoenfield residual plots were assessed to evaluate the constant hazards assumption of the exploratory models over the 150-day observation period.

[0286] Multivariate ER analysis was performed using NONMEM to identify covariates influencing the risk of MALRTI in infants from the Phase 2b study (Table 14). Various parametric distributions, including Weibull and Gompertz, were evaluated during base model development. The Laplacian method was used in NONMEM to determine the objective and log-likelihood functions. Final models were bootstrapped, visual predictive checks were generated, and stratified by relevant covariates.

[0287] [Table 14]

[0288] Simulation Method The final popPK model was used to predict nirsevimab serum PK in late preterm to term infants (GA>35, Phase 3 study) and in preterm infants and children with congenital heart and lung disease (GA<29, CHD / CLD, Phase 2 / 3). Baseline characteristics of the virtual infants were generated by replacement random sampling from Fenton growth charts (Fenton and Kim, 2013 BMC Pediatrics. 13:59-72) or Olsen et al. (2015 Pediatrics 135:e572-81) for preterm infants and from CDC / WHO charts (available on the World Wide Web at www.cdc.gov / growthcharts / who / girls_length_weight.htm) for term to late preterm infants. Of note, the virtual infants were restricted to a minimum postmenstrual age of 36 weeks at baseline to mimic the clinical course of preterm infants. That is, infants would not be dosed until they were clinically stable in the NICU at postmenstrual age ≥ 34 weeks. To capture maturation effects, the imputation algorithm previously described for body weight was used to determine weight changes over time. PK profiles and exposure metrics were summarized and tabulated for hypothetical infants from one RSV epidemic for the Phase 3 cohort and two consecutive epidemics for the Phase 2 / 3 cohort.

[0289] Pharmacokinetic results Patient characteristics The popPK analysis dataset included 3881 serum PK observations from 1090 individuals. Baseline characteristics are outlined in Table 15. Median (range) baseline postnatal and postmenstrual ages ranged from 3 months (0.1-11.9 months) and 13.9 months (7.4-19.7 months), respectively (Figure 9A). Baseline body weight ranged from 1.6 kg to 11.1 kg, with a median of 6.8 kg (Figure 9B). This wide distribution of postnatal and postmenstrual ages and body weights facilitated characterization of the effects of size and maturity on PK parameters. Serum concentrations observed across all studies are shown in Figure 10 and Table 16.

[0290] popPK covariate model The effect of preterm birth on PK parameters was modeled using a first-order exponential function, as shown in Equations 3-4:

number

[0291] Beta CL (β CL ) represents the rate of change in clearance in preterm infants compared to full-term infants, and T50 CL represents the corresponding mature half-life of the parameter for the adult. i represents the sum of each infant's gestational age and postnatal age. The gestational age for adults was set at 40 weeks.

[0292] The final population PK covariate model parameters along with the bootstrap estimates are shown in Table 17. The effect of size and maturity on clearance is shown in FIG.

[0293] Including maturation in the central volume of distribution did not improve model fit, so only allometric scaling was retained for this parameter. Model analysis revealed that the between-subject variance (BSV) was less than 30% for both clearance and volume of distribution. Baseline and time-varying body weight, along with postmenstrual age, were the most influential predictors of clearance.

[0294] Model evaluation Inspection of the goodness-of-fit (Fig. 12, Fig. 13) and visual predictive check (Fig. 14) plots did not reveal any relevant bias or misspecification in the model. Bootstrapping results indicate stability of the final covariate model as all bootstrapped datasets converged successfully. The 95% confidence intervals (CI) for the bootstrap procedure included the original model median estimates for all parameters.

[0295] [Table 15]

[0296] [Table 16]

[0297] [Table 17]

[0298] Exposure-response outcomes Results from the Cox proportional hazards model revealed a positive association between nirsevimab exposure and the risk of lower respiratory tract infection requiring medical care (Figure 15). None of the covariates evaluated in the model violated the constant hazards assumption. Final model and bootstrap parameter estimates are shown in Table 18.

[0299] To further explore these results, a parametric time-to-event analysis was performed in NONMEM. The exponential hazard model adequately described the data as shown by the visual predictive check (VPC) (Figure 16). The effects of geographic region and AUC quartiles on risk of MALRTI were characterized and left in the final covariate model (Figure 17).

[0300] Significant effect of baseline weight on clearance and resulting predicted AUC inf Given this, a rank-based analysis was performed using the Maxstat package in R software to determine optimal cut points along the continuous distribution of weight and weight-normalized dose to facilitate dose optimization for infants with suboptimal exposure (Hothorn and Lausen, 2003 Computational Statistics & Data Analysis. 43(2):525-55). From the analysis, a baseline weight of 4.6 kg was determined to be the optimal weight cut point. Furthermore, exploratory analysis revealed an associated trend toward higher weight for infants with Q1 serum AUC (Figure 18, Figure 19, and Table 19).

[0301] Serum AUC ≥ Q2 was observed in 97% of infants weighing up to 5 kg compared with only 40% of infants weighing ≥ 5 kg. Infants with AUC ≥ Q2 were at lower risk of MALRTI compared with infants who received placebo or had a serum AUC < 13.4 day·mg / mL, hazard ratio (HR) and 95% confidence interval (CI) 0.17 (0.09, 0.32). These results support a dose higher than 100 mg IM in infants with serum AUC < Q1 to match the exposure and resulting benefit observed in infants with serum AUC ≥ Q2 (Figure 20).

[0302] [Table 18]

[0303] [Table 19]

[0304] simulation Baseline characteristics of virtual infants were simulated using CDC / WHO growth charts and data from Olsen et.al. (Pediatrics.2015;135:e572-81) for term and preterm infants. These data were included in the childSDS package v0.6.4 of R software. First, data for virtual infants were resampled from the 3rd to 97th percentile weights for gestational ages ranging from 24 to 40 weeks with a minimum baseline weight of 1.5 kg at dose administration. Simulation data were then assembled to mimic expected populations from Phase 3 trials (GA > 35) and Phase 2 / 3 trials (GA < 29 or CHD / CLD term infants) dosed by 8 months of age. Simulation results (Table 20) further support the proposed dose of 100 mg for infants > 5 kg during the first RSV epidemic. More than 95% of infants are expected to achieve serum AUCs above the target threshold. Mean C for all age groups maxAll were within the safety margin or the previously tolerated exposure range of nirsevimab. Furthermore, PK parameters derived from noncompartmental analysis of the simulated profiles were similar across all age groups and doses, further supporting the appropriateness of the exposure-matching approach to the proposed dosing strategy.

[0305] The proposed doses shown in Table 20 and the expected weight distributions for the first RSV epidemic (Figure 21) and the second RSV epidemic (Figure 23) predict that the AUCs will be similar and generally overlap or exceed the target AUCs for the majority of infants (Figures 22, 24).

[0306] conclusion Based on the exposure-response analysis, nirsevimab doses resulting in a serum AUC of >13.4 days·mg / mL throughout a typical 5-month RSV season are predicted to provide optimal protection against RSV in infants in the first year of life and in high-risk children in the second year of life. Simulations using the final popPK model showed that a single fixed dose of 50 mg (in infants <5 kg) or 100 mg (in infants ≥5 kg) would result in at least 80% of the population having a predicted AUC of >13.4 days·mg / mL during the first RSV season in the first year of life. 0-∞ Furthermore, in children in the second year of life, a single fixed dose of 200 mg nirsevimab is predicted to have a predicted AUC of >13.4 day mg / mL in at least 80% of the population. 0-∞ and is predicted to be safe and effective.

[0307] [Table 20]

[0308] Example 3 Microneutralization assays were performed as follows: Briefly, two-fold serial dilutions of MAbs were introduced into 384-well microtiter plates in HEp-2 cell culture medium at a volume of 15 μL / well. Then, 15 μL of RSV A2 or RSV B9320 virus was diluted in HEp-2 cell culture medium to concentrations ranging from 80 to 150 pfu / well and added to each well, including control wells containing HEp-2 cell culture medium only, and the plates were incubated at 37°C, 5% CO2 for 1.5 hours. HEp-2 cells were cultured at 2.5 × 10 in 30 μL. 5 Cells / mL were added to each well and plates were incubated at 37° C., 5% CO. After 3 days for RSV A2 or 4 days for RSV B9320, media was removed and cells were fixed by adding 30 μL of ice-cold 80% acetone / 20% PBS.

[0309] Viral replication was measured by enzyme-linked immunosorbent assay (ELISA) using horseradish peroxidase-conjugated anti-RSV F MAb targeting the C site of RSV F (1331H) (Beeler and van Wyke Coelingh, J Virol. 63(7):2941-2950 (1989). 1331H MAb was diluted 1:6,000 in PBS and 30 μl was added to each well. After 2 h incubation at 37°C, plates were washed three times with PBS-T. 30 μL of TMB peroxidase was added to each well and plates were incubated for 15 min at room temperature in the dark. The reaction was stopped by adding 15 μL of 2N H2SO4 to each well. Substrate turnover was measured by monitoring absorbance at 450 nm using a microplate reader. Graphpad™ was used to measure the absorbance using log(inhibitor) vs. response with a variable slope curve fit. IC50 values ​​were calculated using a nonlinear fit algorithm in Prism and represent the concentration of MAb required for a 50% reduction in absorbance measured at 450 nm.

[0310] The results are shown in Figure 25, which shows that nirsevimab, 1F5, 2D10, and D25 each inhibited the replication of RSV A2 and RSV B9320 in microneutralization. The sequences of the variable regions of each of these antibodies are shown in Tables 20A and 20B. Nirsevimab was the most effective, followed by 1F5, 2D10, and then D25.

[0311] [Table 21]

[0312] [Table 22]

[0313] Example 4 A cotton rat model was used as described in WO 2015 / 011391. Variants of nirsevimab (1G7-GLM, B12-1, E3-5, and E9-2) were generated to alter the isoelectric point (pI) by incorporating germline residues in the heavy chain of the antibody. The sequences of the heavy chain variable regions of these variants are shown in Table 21; residues marked with "~" indicate the modifications made to nirsevimab.

[0314] Concentrations of human IgG in cotton rat serum samples on the day of lung removal were measured using an ELISA method. Human antibodies were captured with goat anti-human antibodies bound to microtiter plates. Goat anti-human IgG (H+L) antibodies (0.5 μg / mL in 1× PBS) were coated on Nunc Maxisorp 384-well microtiter plates in a volume of 30 μL overnight at 4°C. Plates were washed and then blocked with a solution of 60 μL of PBS + 3% heat-inactivated goat serum for 1 hour at room temperature. Blocking buffer was removed and samples were fitted as follows: 2-fold serial dilutions of standard human antibodies diluted in assay buffer were used for the standard curve with a concentration range of 500 ng / ml to 0.488 ng / ml. Standard curves were fitted using a 4 parameter curve fit.

[0315] The results are shown in Figure 26. The results show that the variants described herein have a lower IC50 than D25 in neutralizing both RSV A2 and RSV B9320. It also shows that there is no loss of activity against A2 or B9320 viruses, E9-2 and B12-1 show increased activity, and only 1G7 GLM and E3-5 show a slight loss of activity against B9320 virus.

[0316] [Table 23]

[0317] The complete disclosures of all patents, patent applications, and publications cited herein, as well as electronically available materials (including nucleotide sequence entries, such as GenBank and RefSeq, and amino acid sequence entries, such as SwissProt, PIR, PRF, PDB, and translations from annotated coding regions in GenBank and RefSeq) are incorporated by reference. In the event of any inconsistency between the disclosure of this application and the disclosure of any document incorporated herein by reference, the disclosure of this application shall control. The foregoing detailed description and examples have been given for clarity of understanding only. No unnecessary limitations should be construed therefrom. The invention is not limited to the exact details shown and described, and variations that are obvious to one skilled in the art are included within the invention defined by the claims.

Claims

1. 1. A method for treating or preventing an RSV infection in a patient in need thereof, comprising: determining the age of the patient; administering to said patient in the second year of life a fixed dose of 200 milligrams (mg) of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof; Determining the patient's weight corresponding to the patient's first year of life; and administering a fixed dose of 100 mg of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof to said patient having a body weight of at least 5 kilograms (kg); Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both.

2. 1. A method of treating or preventing an RSV infection in a patient in need thereof, comprising administering to a patient having a body weight of at least 5 kilograms (kg) a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both.

3. 1. A method for treating or preventing an RSV infection in a patient in need thereof, comprising: Determining the patient's weight; Administering to a patient having a body weight of at least 5 kilograms (kg) a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both; Administering a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient weighing up to 5 kg, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both. The method includes:

4. 1. A method for treating or preventing an RSV infection in a patient in need thereof, comprising: Determining the age of the patient; and Administering to a patient 3 months of age or older a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both. The method includes:

5. 1. A method for treating or preventing an RSV infection in a patient in need thereof, comprising: Determining the patient's age; administering a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient 3 months of age or older; administering a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to patients up to 3 months of age; Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both.

6. 1. A method for treating or preventing an RSV infection in a patient in need thereof, comprising: Determining the patient's age; administering to a patient 6 months of age or older a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof; administering a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to patients up to 6 months of age; Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both.

7. 1. A method for treating or preventing an RSV infection in a patient in need thereof, comprising: determining whether the patient is experiencing a first or second RSV swarm; administering to said patient experiencing said second RSV season a fixed dose of 200 milligrams (mg) of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof; Determining the patient's body weight corresponding to the patient experiencing the first RSV season; and administering a fixed dose of 100 mg of a composition comprising an anti-RSV monoclonal antibody or antigen-binding fragment thereof to said patient having a body weight of at least 5 kilograms (kg); Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both.

8. 1. A method for treating or preventing an RSV infection in a patient in need thereof, comprising: determining whether the patient is experiencing a first or second RSV swarm; Administering a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient experiencing a second RSV pandemic, wherein the anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both. The method includes:

9. 1. A method for treating or preventing an RSV infection in a patient in need thereof, comprising: determining whether the patient is experiencing a first or second RSV swarm; administering to a patient a fixed dose of 200 milligrams (mg) of an anti-RSV monoclonal antibody or antigen-binding fragment thereof, wherein the patient is experiencing a second RSV pandemic; administering a fixed dose of 100 mg of an anti-RSV monoclonal antibody or antigen-binding fragment thereof to a patient, wherein the patient is experiencing a first RSV pandemic. Including, The anti-RSV monoclonal antibody or antigen-binding fragment thereof has an IC50 of 5.0 ng / ml or less in an RSV A neutralization assay, or an IC50 of 3.0 ng / ml or less in an RSV B9320 neutralization assay, or both.

10. The method of any one of claims 1 to 9, wherein the anti-RSV monoclonal antibody comprises nirsevimab, or the antigen-binding fragment of the anti-RSV monoclonal antibody comprises an antigen-binding fragment of nirsevimab.

11. administering the anti-RSV monoclonal antibody or antigen-binding fragment thereof in a composition comprising an ionic excipient, a buffer, a sugar, and a surfactant; The ionic excipient comprises L-arginine hydrochloride at a concentration of 80 mM; The buffer contains 30 mM L-histidine / L-histidine hydrochloride, the sugar comprises 120 mM sucrose; The surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v); and The method according to any one of claims 1 to 10, wherein the composition has a pH in the range of 5.5 to 6.

5.

12. A pharmaceutical composition for treating or preventing RSV infection, comprising 100 mg of nirsevimab, administered to a patient in the first year of life or experiencing their first RSV circulating season, said patient having a body weight of at least 5 kg.

13. A pharmaceutical composition for treating or preventing RSV infection, comprising 200 mg of nirsevimab, administered to a patient in the second year of life or a patient experiencing a second RSV plague season.

14. The patient has an AUC of greater than 13.4 day-mg / mL. ０－∞ The pharmaceutical composition according to claim 12 or 13,

15. further comprising ionic excipients, buffers, sugars, and surfactants; The ionic excipient comprises L-arginine hydrochloride at a concentration of 80 mM; The buffer contains 30 mM L-histidine / L-histidine hydrochloride, the sugar comprises 120 mM sucrose; The surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v); and The pharmaceutical composition according to any one of claims 12 to 14, wherein the composition has a pH in the range of 5.5 to 6.

5.

16. A pharmaceutical unit dose comprising 100 mg of nirsevimab, said pharmaceutical unit dose being suitable for intramuscular administration.

17. A pharmaceutical unit dose comprising 200 mg of nirsevimab, said pharmaceutical unit dose being suitable for intramuscular administration.

18. The pharmaceutical unit dose comprising nirsevimab is contained in a composition, the composition further comprising an ionic excipient, a buffer, a sugar, and a surfactant; The ionic excipient comprises L-arginine hydrochloride at a concentration of 80 mM; The buffer contains 30 mM L-histidine / L-histidine hydrochloride, the sugar comprises 120 mM sucrose; The surfactant comprises polysorbate 80 in the range of 0.01% (w / v) to 0.05% (w / v); and The pharmaceutical unit dose of claim 16 or 17, wherein the composition has a pH in the range of 5.5 to 6.

5.

19. The pharmaceutical unit dose of any one of claims 16 to 18, wherein the nirsevimab in the composition is stable at 2°C to 8°C for at least 3 months as measured by high performance size exclusion chromatography (HPSEC).

20. The pharmaceutical unit dose of any one of claims 16 to 19, wherein the nirsevimab is present in a concentration of 100 mg / mL.

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