Methods for enhancing vaccine efficacy by administering an IL-4R antagonist

Abstract

Pharmaceutical compositions for use in methods for reducing vaccine-specific IgE induced by a vaccine against a bacterial or viral infection are provided. The IL-4R antagonist is administered simultaneously with or within 24 hours of administering the vaccine.

Description

[Technical Field]

[0001] Sequence Listing Reference This application incorporates by reference the Sequence Listing, which was filed in computer readable format as file 10209WO01-Sequence.txt, created on February 10, 2017, and contains 15,276 bytes.

[0002] The present invention relates to methods for increasing the effectiveness of vaccines. More particularly, the present invention relates to the administration of an interleukin-4 receptor (IL-4R) antagonist in combination with a vaccine to a subject in need thereof. [Background technology]

[0003] Vaccines are one of the most successful public health interventions in preventing disease and deaths due to infectious diseases. Vaccines typically contain disease-causing agents, their products, or surrogates that act as antigens without causing disease (or, in some cases, mild disease). For example, some current vaccines against microbial pathogens consist of live-attenuated or avirulent variant strains of microorganisms, or killed or otherwise inactivated organisms. Other vaccines utilize pathogen lysates, such as surface carbohydrates, recombinant pathogen-derived proteins sometimes fused to other molecules, or more or less purified components of replicating viruses that produce pathogen-derived antigens. Vaccines function by activating antigen-specific naive lymphocytes, which then induce an internal immune response that generates antibody-secreting B cells or antigen-specific effector and memory T cells, or both. This approach can result in long-lasting protective immunity that can be boosted from time to time by renewed exposure to the same antigenic material.

[0004] Vaccines generally contain adjuvants that help accelerate, prolong, and / or enhance antigen-specific immune responses. Some commonly used adjuvants include, but are not limited to, aluminum salts (e.g., alum, aluminum phosphate, and aluminum hydroxide), Freund's complete adjuvant, Freund's incomplete adjuvant, Ribi adjuvant, squalene, and MF59®.

[0005] There remains a need for safe and effective vaccines and / or improved vaccination strategies that enhance efficacy and provide more durable protection against pathogen exposure and challenge without causing any adverse side effects (e.g., allergic reactions). Summary of the Invention

[0006] According to certain aspects of the present invention, methods are provided for enhancing the efficacy and / or safety of a vaccine in a subject. Methods of increasing the immune response to a vaccine or increasing the duration of protective immunity of a vaccine in a subject are also included. In certain embodiments, the present invention provides methods for increasing protection against disease in a subject, and / or for preventing infection and the spread of the aforementioned disease to uninfected subjects, or for preventing the progression of a disease to another disease. Methods according to these aspects include administering to a subject in need thereof an interleukin-4 receptor (IL-4R) antagonist in combination with a vaccine. In certain embodiments, the method comprises selecting a subject susceptible to a microbial infection, and administering to the subject in need thereof an interleukin-4 receptor (IL-4R) antagonist. The administration of L-4R antagonists in combination with vaccines against the aforementioned microbial infections is In certain embodiments, the IL-4R antagonist comprises It may be administered before, after, or simultaneously with a vaccine in a subject.

[0007] According to certain aspects, the present invention provides methods for preventing, treating, reducing, or ameliorating adverse side effects of a vaccine (e.g., an allergic reaction) in a subject in need thereof. In certain embodiments, the present invention provides methods for preventing, reducing, or ameliorating a vaccine-induced T helper 2 (Th2) response in a subject in need thereof. In certain embodiments, the present invention provides methods for reducing vaccine-induced IgE in a subject in need thereof. Methods according to these aspects include administering an IL-4R antagonist in combination with a vaccine to a subject in need thereof. This includes administering.

[0008] According to certain embodiments, the present invention provides for the use of an IL-4R antagonist in combination with the aforementioned vaccines. and administering to a subject in need thereof. In certain embodiments, the total number of vaccine doses is reduced by administering to a subject in need thereof an IL-4R antagonist. The dose is reduced by one or more doses, e.g., one dose, two doses, or more, compared to a subject not receiving the compound.

[0009] According to certain aspects, the present invention provides methods for treating atopic dermatitis in a patient without interfering with the patient's response to a vaccine. In certain embodiments, the present invention provides methods for treating atopic dermatitis in a patient without suppressing the patient's response to a vaccine. The methods according to these aspects include selecting a patient diagnosed with atopic dermatitis who has recently received or will receive a vaccine; and administering one or more doses of an IL-4R antagonist to the patient, wherein the IL-4R antagonist does not reduce or attenuate the patient's response to the vaccine. In certain embodiments, administration of the IL-4R antagonist is performed in accordance with Investigator's Global Assessment (IGA); atopic dermatitis body surface area lesions (BSA); eczema area and severity index (EASI); atopic dermatitis assessment score (SCORAD); 5-D pruritus scale; and pruritus numerical rating. The vaccine results in an improvement in one or more atopic dermatitis (AD)-related parameters selected from the group consisting of the National Rats Scale (NRS). In certain embodiments, patients with atopic dermatitis are susceptible to microbial infections, such as whooping cough, diphtheria, tetanus, tuberculosis, meningitis, etc. In certain embodiments, patients with atopic dermatitis are allergic to certain components of the vaccine or develop an allergic reaction (e.g., a skin reaction) to the vaccine. In certain embodiments, the patient is a child under about 3 years of age who has been diagnosed with atopic dermatitis and is in need of a vaccine against an infectious disease (e.g., whooping cough).

[0010] In certain embodiments, the vaccine is directed against Bordetella pertussis, Corynebacterium diptheriae, Clostridium tetani, Mycobacterium tuberculosis, Plasmodium spp., Bacillus anthracis, Vibrio cholera, Salmonella typhi, Borrelia spp., Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, coli), Clostridium species, Mycobacterium leprae, Yersinia Yersinia pestis, influenza virus, varicella zoster virus, human and is caused by a microorganism selected from the group consisting of human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), poliovirus, smallpox virus, rabies virus, rotavirus, human papillomavirus, Ebola virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, lyssavirus, measles virus, mumps virus, and rubella virus. It is for diseases or infections caused by

[0011] In certain embodiments, the vaccine is against a disease or infection selected from the group consisting of whooping cough, diphtheria, tetanus, tuberculosis, malaria, anthrax, cholera, typhoid, leprosy, Lyme disease, streptococcal infection, E. coli infection, staphylococcal infection, plague, clostridial infection, meningococcal infection, pneumococcal infection, pneumonia, meningitis, sepsis, influenza, chickenpox, HIV infection, RSV infection, polio, smallpox, rabies, rotavirus infection, papilloma, cervical cancer, Ebola, hepatitis, yellow fever, measles, mumps, and rubella infection. According to one embodiment, the vaccine is against whooping cough.

[0012] According to certain embodiments, the methods of the present invention involve administering to a subject a therapeutic agent comprising one or more IL-4R antagonists. In certain embodiments, one or more doses of an IL-4R antagonist are administered, and wherein each dose is administered 1 to 12 weeks after the immediately preceding dose. In certain embodiments, each dose of the IL-4R antagonist comprises 1 to 50 mg per kg of the subject's body weight. In certain embodiments, each dose of IL-4R antagonist contains 10-600 mg of IL-4R antagonist. In certain embodiments, each dose contains 0.1-10 mg per kg of subject body weight. In certain embodiments, one or more doses of vaccine are administered, where each dose is administered 2-24 months after the immediately preceding dose. In certain embodiments, one or more doses of vaccine are administered at intervals of 2-15 years after the immediately preceding dose. In certain embodiments, subsequent doses of vaccine are referred to as "booster" doses. In certain embodiments, the method includes administering one or more doses of IL-4R antagonist. Multiple doses administered prior to each dose of vaccine, followed by an IL-4R antagonist dose In a further embodiment, the method optionally comprises administering one or more doses of an IL-4R antagonist after administering the vaccine dose. This includes:

[0013] In certain embodiments, the methods of the invention involve administering from about 10 mg to about 10 mg of an IL-4R antagonist. This involves administering an initial dose of about 600 mg, followed by one or more secondary doses. In certain embodiments, the initial dose and the one or more secondary doses each comprise about 10 mg to about 600 mg of the IL-4R antagonist. The IL-4R antagonist is administered at a starting dose of 600 mg, followed by one or more secondary doses. is administered, wherein each secondary dose contains 300 mg. The IL-4R antagonist is administered at an initial dose of 400 mg, followed by one or more secondary doses, where each secondary dose contains 200 mg. In certain embodiments, the initial and one or more secondary doses each contain 0.1 to 10 mg / kg of IL-4R antagonist. In certain embodiments, the initial and one or more secondary doses each comprise 1, 2, 3, 5, or 6 mg / kg of the IL-4R antagonist. According to an embodiment, the IL-4R antagonist is administered to the subject, e.g., once a week, once every two weeks, The vaccine may be administered at a dosing frequency of once every 3 weeks, once every 4 weeks, or once every 4 weeks. In one embodiment, each secondary dose is administered one week after the immediately preceding dose. In certain embodiments, the vaccine is administered at an initial dose followed by one or more subsequent (booster) doses, where each subsequent (booster) dose is administered 1 to 104 weeks after the immediately preceding dose. In certain embodiments, the one or more subsequent (booster) doses are administered 2 to 20 years after the immediately preceding dose.

[0014] In certain embodiments, the IL-4R antagonist is administered to a subject in need thereof. In certain embodiments, one or more doses of an IL-4R antagonist are administered before, after, or at the same time as each dose of a vaccine. In certain embodiments, one or more IL-4R antagonists are administered simultaneously. The amount is administered before each dose of vaccine. In certain embodiments, one or more doses of an IL-4R antagonist are administered before each dose of the vaccine, followed by one or more doses of an IL-4R antagonist. wherein the IL-4R antagonist dose is administered simultaneously with the vaccine dose, and optionally Subsequently, one or more doses of an IL-4R antagonist are administered after vaccination.

[0015] According to certain embodiments, the present invention provides a vaccination regimen in a subject, comprising the administration of a starting dose of a vaccine, optionally followed by the administration of one or more subsequent booster doses, wherein the administration of each vaccine dose is preceded by the administration of one or more doses of an IL-4R antagonist. In certain embodiments, the method comprises administering a dose of an IL-4R antagonist together with the aforementioned vaccine, followed by administration of one or more doses of the IL-4R antagonist. The dose or doses of the 4R antagonist are administered at weekly, biweekly, triweekly, or 4-weekly intervals following the immediately preceding dose.

[0016] Exemplary IL-4R antagonists that can be used in the context of the methods of the present invention For example, the small molecule IL-4R or its ligands (IL-4 and / or IL-13) Chemical inhibitors of the molecule or biological agents that target IL-4R or its ligands According to certain embodiments, the IL-4R antagonist is an antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) that binds to the IL-4R α chain and blocks signaling by IL-4, IL-13, or both IL-4 and IL-13. In one embodiment, an antibody or antigen-binding fragment thereof that specifically binds to IL-4R is , and the complementarity determining regions (CDRs) in the heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair of SEQ ID NOs: 1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain CDR (HCDR1) having the amino acid sequence of SEQ ID NO: 3, an HCDR2 having the amino acid sequence of SEQ ID NO: 4, an HCDR3 having the amino acid sequence of SEQ ID NO: 5, a light chain CDR (LCDR1) having the amino acid sequence of SEQ ID NO: 6, an LCDR2 having the amino acid sequence of SEQ ID NO: 7, and an LCDR3 having the amino acid sequence of SEQ ID NO: 8. One such type of antigen-binding protein that can be used in the context of the methods of the present invention is an anti-IL-4Rα antibody, such as dupilumab.

[0017] In some embodiments, the IL-4R antagonist is administered to the subject subcutaneously, intravenously, or intravenously. is administered intraperitoneally.

[0018] According to certain aspects, the present invention provides vaccine compositions comprising an adjuvant, wherein the adjuvant comprises an IL-4R antagonist. The cutin composition further comprises a vaccine component selected from the group consisting of tetanus toxoid, diphtheria toxoid, inactivated pertussis toxin, filamentous hemagglutinin, pertactin, type 2 fimbriae, type 3 fimbriae, and formalin-inactivated respiratory syncytial virus. In certain embodiments, the vaccine composition comprises a second adjuvant (e.g., alum).

[0019] In certain embodiments, the present invention provides for the use of an IL-4R antagonist of the present invention in the manufacture of a medicament for enhancing the efficacy and / or safety of a vaccine in a patient. In certain embodiments, the present invention provides the use of an IL-4R antagonist in a method for increasing the efficacy and / or safety of a vaccine, wherein the IL-4R antagonist is administered to a subject in need thereof in combination with the aforementioned vaccine.

[0020] Other embodiments of the present invention will become apparent from the following detailed description. [Brief explanation of the drawings]

[0021] [Figure 1] 1 shows the study design, including dosing and sampling schedules, for the studies in Examples 1, 2, 3, or 4. [Figure 2] Figures 2A and 2B show serum total IgE levels in mice immunized with either TDaP containing acellular pertussis (aP) vaccine (Figure 2A) or DTP containing whole-cell pertussis (wP) vaccine (Figure 2B) and treated with an isotype control antibody or an anti-mouse IL-4R antibody (anti-IL-4Rα). Results are for 4 to 12 mice per group. One-way ANOVA statistical analysis was performed: ***p<0.001, ****p<0.0001. [Figure 3]Figures 3A and 3B show (Figure 3A) the filamentous hemagglutinin (FHA)-specific total IgG titer in aP-immunized mice, and (Figure 3B) the heat-killed Bordetella pertussis (HKBp)-specific total IgG titer in wP-immunized mice. Results are for 4 to 12 mice per group. *p<0.05, ****p<0.0001. [Figure 4] Figures 4A and 4B show (Figure 4A) FHA-specific IgG1 titers in aP-immunized mice and (Figure 4B) HKBp-specific IgG1 titers in wP-immunized mice. Results are for 4 to 12 mice per group. One-way ANOVA statistical analysis was performed. **p<0.01, ***p<0.001, ****p<0.0001. [Figure 5] Figures 5A and 5B show (Figure 5A) FHA-specific IgG2a titers in aP-immunized mice and (Figure 5B) HKBp-specific IgG2a titers in wP-immunized mice. Results are average values ​​for 4 to 12 mice per group. One-way ANOVA statistical analysis was performed. **p<0.01, ***p<0.001, ****p<0.0001. [Figure 6] Figures 6A and 6B show (Figure 6A) FHA-specific IgG2c titers in aP-immunized mice and (Figure 6B) HKBp-specific IgG2c titers in wP-immunized mice. Results are for 4 to 12 mice per group. One-way ANOVA statistical analysis was performed. *p<0.05, ****p<0.0001. [Figure 7] This shows that anti-IL-4Rα treatment in aP-immunized mice enhances FHA-specific interferon-gamma (IFN-γ) production by splenocytes upon restimulation. Results are average values ​​for four mice per group. Two-way ANOVA statistical analysis was performed: ***p<0.001. [Figure 8]Figures 8A and 8B show the total number of B. pertussis colony-forming units (CFU) per lung in mice immunized with either two doses of aP (Figure 8A) or wP (Figure 8B) and challenged with B. pertussis by aerosol exposure, as described in the study in Example 4. Results are the mean values ​​for 4 to 8 mice per group at each time point (except for the wP-immunized group (B) on day 14, n = 3). ***p<0.001 by two-way ANOVA, aP + control IgG vs. aP + anti-IL-4Rα. [Figure 9] 1 shows the study design, including dosing and sampling schedules, for the study in Example 5. [Figure 10] Figure 1 shows the total number of B. pertussis colony-forming units (CFU) per lung in mice immunized with one dose of either aP or wP vaccine and challenged with B. pertussis by aerosol exposure, as described in the study in Example 5. Results are the mean values ​​for four mice per group at each time point (except for the untreated group on day 7, n=3). By two-way ANOVA, ***p<0.001, aP+control IgG vs. aP+anti-IL4Ra; ΔΔΔp<0.001, aP+control IgG vs. wP+control IgG. DETAILED DESCRIPTION OF THE INVENTION

[0022] Before the invention is described, it is to be understood that the invention is limited to the particular methods and experimental conditions described. It is to be understood that methods and conditions may vary. The scope of the present invention will be limited only by the appended claims, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. As used herein, the term "about" when used in connection with a specific referenced numerical value means that the value may differ from the referenced value by less than 1%. For example, as used herein, the expression "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.). As used herein, the terms "treat," "treating," etc. mean to alleviate symptoms, remove the cause of symptoms, either temporarily or permanently, or prevent or delay the appearance of the symptoms of the named disorder or condition.

[0024] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference and are set forth in their entirety.

[0025] General Description Bacillus pertussis is a gram-negative bacterium that causes pertussis (also known as whooping cough), a highly contagious, severe, and sometimes fatal respiratory infection in infants and young children. Pertussis was largely controlled after the introduction of the whole-cell pertussis (wP) vaccine (DTP or DPT) in 1943. wP vaccines typically contain an inactivated (heat-killed or chemically treated, usually with formalin) suspension of the whole bacterial organism. However, wP vaccines have been found to be associated with a variety of adverse side effects, including vaccine-induced fever, febrile seizures, and central nervous system complications. Therefore, the wP vaccine was discontinued in the United States due to safety concerns and was completely replaced by the acellular pertussis (aP) vaccine in 1997. The aP vaccine contains inactivated pertussis toxin (PT) and one or more other bacterial components [i.e., filamentous hemagglutinin (FHA), pertactin (Pn), and fimbriae (Fim)] precipitated in alum and has been widely used in developed countries since 1990. However, since the aP vaccine replaced the wP vaccine, pertussis has reemerged as a public health concern. Reported pertussis cases among children aged 7 to 10 years increased from 13% to 23% of reported cases, which was equivalent to the 42,000 cases of pertussis reported in children in 2012 (Mills et al. 2014; Trends Microbiol. 22: 49-52).

[0026] The mechanisms contributing to protective immunity have been studied for wP and aP vaccines in humans and in mouse models. The immune responses observed with wP vaccines closely resemble those of naturally infected individuals or challenged mice. wP induces a T helper 1 (Th1) response (i.e., neutrophil influx and IL-1 and IL-12 production) (Redhead et al. 1993, Infect. Immun. 61: 3190-8; Ross et al. 2013, PLoS Pathog 9(4): e1003264.doi:10.1371 / journal.ppat.1003264). However, wP also induces IgE formation and allergic reactions. On the other hand, aP vaccine induces a well-defined T helper 2 (Th2) response in both humans and preclinical mouse models, where the Th2 response is induced via IL-4 production (Mills et al 1998, Infect. Immun. 66: 596-602). Subsequent studies have shown that Th2 responses are predominant in humans and mouse models. that HIV vaccination and previous infection are not essential for protective immunity, and that they Because it induces a Th1 response, it has been shown to be better than the current aP vaccine in obtaining protective immunity (Ross et al. 2013, PLoS Pathog 9(4): e1003264.doi:10.1371 / journal.ppat.1003264; Brummelman et al. 2015, FEMS Pathog. Dis. doi: 10.1093 / femspd / ftv067). The aP vaccine fails to generate effective immunological memory, which leads to waning protective immunity. In addition, the Th2 response elicited by the aP vaccine leads to undesirable IgE and rare hypersensitivity reactions observed in children with the fourth or fifth booster dose (Brummelman et al. 2015, FEMS Pathog. Dis. doi: 10.1093 / femspd / ftv067). Furthermore, antigenic variation has been observed in pertussis toxin, pertactin and fimbriae, which leads to loss of protection against some currently circulating strains (Brummelman et al 2015, FEMS Pathog. Dis. doi: 10.1093 / femspd / ftv067).

[0027] A novel animal model of experimental pertussis in baboons revealed a major deficit in protective immunity induced by aP vaccination (Warfel et al. 2014, PNAS 111: 787). The study showed that animals with previous infection were not colonized after aerosolized challenge, while the wP vaccine prevented disease and enhanced bacterial clearance compared to naive animals. In contrast, the aP vaccine produced a suboptimal immune response that prevented disease in vaccinated baboons but failed to prevent infection or transmission to naive baboons.

[0028] Various molecules, e.g., cytokines such as IL-1, IL-12, and GM-CSF, and Toll-like receptor agonists are being investigated as potential adjuvants to potentially increase the immunogenicity and duration of immunity provided by aP vaccines (Dunne et al 2015, Mucosal Immunol. 8: 607-17; Allen & Mills 2014, Expert Rev. Vaccines 13: 1253-64). There remains an unmet need for improved vaccine compositions and vaccination strategies to prevent Bordetella pertussis infection and transmission. The inventors herein describe the use of IL-4R antagonists in combination with aP vaccines. Administration of a steroid (e.g., anti-IL-4R antibody) induces more Th1-type antigen-specific IgG antibodies. These results show that IL-4R antagonists (e.g., anti-IL-4R antibodies) result in the production of isotypic antibodies (e.g., IgG2a and b / c in mice, or IgG1 in humans) and a reduction in IgE and Th2-type antigen-specific IgG isotypic antibodies (e.g., IgG1 in mice, or IgG4 in humans), thereby providing better protection in response to pathogen challenge. More generally, as shown herein, administration of an IL-4R antagonist (e.g., an anti-IL-4R antibody) as an adjuvant in combination with a vaccine generates a Th1 response instead of a Th2 response, thereby ensuring better vaccine efficacy and / or preventing adverse side effects of the vaccine (e.g., allergic reactions).

[0029] Methods for enhancing vaccine efficacy and / or safety The present invention provides a vaccine to a subject in need thereof, a pharmaceutical composition comprising an L-4R antagonist, and The present invention also includes a method of administering a pharmaceutical composition comprising an IL-4R antagonist in combination with a pharmaceutical composition comprising an IL-4R antagonist. The composition comprises a pharmaceutically acceptable carrier or excipient. In certain embodiments, the IL-4R antagonist is administered before, after, and / or simultaneously with the vaccine.

[0030] As used herein, the expression "subject in need thereof" refers to a human or non-human animal susceptible to and / or in need of prophylactic protection from microbial (e.g., bacterial or viral) infections.In the context of the present invention, the term "subject" refers to a human or non-human animal susceptible to and / or in need of prophylactic protection from microbial (e.g., bacterial or viral) infections, including pertussis, diphtheria, tetanus, tuberculosis, malaria, anthrax, cholera, typhoid, leprosy, Lyme disease, streptococcal infection, E. coli infection, staphylococcal infection, plague, clostridial infection, meningococcal infection, pneumococcal infection, pneumonia, meningitis, sepsis, influenza, chickenpox, HIV infection, RSV infection, polio, smallpox, rabies, rotavirus infection, papilloma, cervical cancer, Ebola, hepatitis, yellow fever, measles, Included are subjects susceptible to an infection selected from the group consisting of mumps and rubella infections.

[0031] In some embodiments, the term "subject" includes children who are 3 years of age or younger. For example, the methods may be used for infants who are less than 1 month, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months of age. In other embodiments, the methods of the invention may be used to treat children who are about 1 year old, under 1 year old, under 2 years old, under 3 years old, under 4 years old, under 5 years old, under 6 years old, under 7 years old, under 8 years old, under 9 years old, under 10 years old, under 11 years old, under 12 years old, under 13 years old, under 14 years old, or under 15 years old. In certain embodiments, the methods of the invention may be used to treat adolescents who are about 15 years old, about 16 years old, about 17 years old, about 18 years old, about 19 years old, about 20 years old, or under 20 years old.

[0032] In certain embodiments, the term "subject" includes adults who are over 50, over 55, over 60, over 65, over 70, or over 75 years of age.

[0033] In certain embodiments, the term "subject" includes adults who are over the age of 20, over 25, over 30, over 35, over 40, over 45, or over 50. In certain embodiments, the adult has not been previously immunized with a vaccine such as a tetanus vaccine, a diphtheria vaccine, or a pertussis vaccine.

[0034] In certain embodiments, the term "subject" includes adults or adolescents over the age of 10 who have been immunized with a vaccine but do not need to receive a booster dose of the vaccine. In certain embodiments, the term includes adults who may have been previously immunized but who have developed compromised immunity to an infectious disease and need to receive an additional vaccine dose (e.g., a booster dose). In certain embodiments, the term "subject" includes subjects who are allergic to one or more components of the vaccine. In further embodiments, the term includes subjects who may be at increased risk of developing an allergic response to the vaccine.

[0035] In certain embodiments, the present invention provides a method for administering one or more doses of the aforementioned vaccine to an IL-4R Methods of enhancing the efficacy and / or safety of a vaccine are provided, comprising administering to a subject in need thereof in combination with one or more doses of an antagonist.

[0036] In certain embodiments, the present invention provides a method for administering one or more doses of the aforementioned vaccine to a mammalian animal, comprising administering to the mammal an IL-4 The present invention provides a method of enhancing or potentiating the immune response to a vaccine comprising administering to a subject in need thereof in combination with one or more doses of an R antagonist.

[0037] As used herein, the term "enhancing the efficacy and / or safety of a vaccine" refers to the increased efficacy and / or safety of a vaccine compared to the administration of a vaccine alone, which increases the efficacy and / or safety of a vaccine by IL-4R antagonists in response to a subsequent pathogen challenge. "Protein-specific protection" refers to the increased protection and / or increased duration of protection provided by administration of a vaccine in combination with an antagonist. In certain embodiments, the term includes one or more of the following: (a) prevention of disease caused by pathogenic bacteria or viruses; (b) reduced bacterial or viral titers in infected hosts or reduced pathogen burden in infected hosts; (c) faster clearance of pathogens from infected hosts; (d) increased production of pathogen-specific Th1-type IgG isotype titers; (e) reduced or suppressed allergic responses resulting from vaccine administration; (f) reduced or inhibited production of serum IgE in hosts resulting from vaccine administration; (g) a reduction in Th2 responses; (h) reduced production of pathogen-specific Th2-type IgG isotype titers; (i) a reduction in the total number of vaccine doses required for protection; (j) prevention of pathogen infection and spread and / or infectious disease; and / or (k) long-lasting (durable) resistance to subsequent pathogen challenges, compared to subjects administered the vaccine alone. In certain embodiments, the term vaccine In certain embodiments, the term includes preventing or reducing or suppressing one or more IgE-mediated responses to a vaccine, including, but not limited to, urticaria, angioedema, anaphylaxis, gastrointestinal disorders, and discontinuing a booster dose of a vaccine that results in a suboptimal immune response to the vaccine. In one aspect, the present invention provides for the use of an IL-4R antagonist in combination with a vaccine to treat a patient in need thereof. The present invention provides a method for generating an optimal immune response to a vaccine in a subject, comprising administering to the subject a vaccine ...

[0038] According to one aspect, the present invention provides a method for preventing infection and / or transmission of an infectious disease to a subject. In certain embodiments, the present invention provides a method for increasing herd immunity in a population susceptible to an infectious disease. The method according to this aspect comprises administering to a subject an IL-4R This involves administering the antagonist in combination with a vaccine to a subject in need thereof.

[0039] In certain embodiments, the present invention provides methods for preventing, treating, or reducing or ameliorating the severity of adverse side effects induced by administration of a vaccine in a subject in need thereof. Adverse side effects induced by vaccines include, but are not limited to, injection site reactions, allergic reactions, localized swelling, swollen lymph nodes, and hypersensitivity. In certain specific embodiments, the present invention provides methods for preventing, treating, or reducing or lessening the severity of allergic responses induced by administration of a vaccine in a subject in need thereof. As used herein, the phrases "allergic response," "allergic reaction," "allergic symptoms," and the like, include, but are not limited to, urticaria (e.g., hives), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinusitis, watery eyes, asthma, and the like. The term "allergic response" includes one or more signs or symptoms selected from the group consisting of tinnitus, bronchospasm, reduced peak expiratory flow (PEF), gastrointestinal disorders, flushing, swollen lips, swollen tongue, reduced blood pressure, anaphylaxis, and organ damage / failure. "Allergic response," "allergic reaction," "allergic symptoms," etc. also include immunological responses and reactions, such as increased Th2 response, increased IgE production, and / or increased allergen-specific immunoglobulin production. As used herein, the term "reducing allergic response" refers to the absence of an allergic response or a reduction in the severity of an allergic response.

[0040] In certain embodiments, the present invention provides a vaccine comprising one or more doses of an IL-4R antagonist. The present invention also includes a method for reducing total serum IgE levels induced by administration of a vaccine, comprising administering the vaccine in combination with one or more doses of an IL-4R antagonist. As used herein, a reduction in serum IgE levels is defined as a reduction in serum IgE levels in a patient who has been administered a vaccine and treated with an IL-4R antagonist. The amount of IgE measured in the serum of subjects treated with an IL-4R antagonist was "Decreased serum IgE levels" refers to serum IgE levels that are at least 5%, 10%, 20%, 50%, 80%, or 90% lower than serum IgE levels measured in the same or comparable subjects without the allergy. In certain embodiments, a reduction in serum IgE levels means that no or negligible amounts of IgE are detected in the serum of a subject. As used herein, serum IgE may include total serum IgE and / or antigen-specific IgE (e.g., allergen-specific IgE).

[0041] In certain embodiments, the present invention provides a vaccine comprising one or more doses of an IL-4R antagonist. The present invention provides a method for reducing a Th2 response induced upon administration of a vaccine in a subject in need thereof, comprising administering the method in combination with one or more doses of an agonist. In certain embodiments, reducing the Th2 response includes, but is not limited to, a reduction in vaccine-induced serum IgE levels and / or reduced production of pathogen-specific Th2-type IgG isotype titers (e.g., IgG1 in mice or IgG4 in humans).

[0042] The present invention includes a method for reducing susceptibility to an allergic response to a vaccine in a subject. As used herein, the term "subject" refers to a subject with increased susceptibility or at higher risk of developing an allergic response, such as a subject with atopic dermatitis. In this embodiment, the term "subject" includes a subject with atopic dermatitis, a subject with increased allergen sensitization, and a subject with allergic rhinitis, asthma, or food allergy. In certain embodiments, the present invention provides a method for reducing susceptibility to an allergic response to a vaccine in a subject. and a method for reducing toxicity associated with vaccination in a patient with atopic dermatitis, the method comprising administering one or more doses of the compound in combination with the aforementioned vaccine. The term "subject" also includes subjects with elevated levels of serum total and allergen-specific IgE, or serum chemokines (e.g., CCL17 or CCL27).

[0043] According to certain aspects, the present invention includes a method for increasing the duration of vaccine-induced immunity in a subject in need thereof. It is known in the art that some vaccines, e.g., acellular pertussis vaccines, exhibit shorter durations of protection, thereby requiring regular booster doses in subjects such as older children, adolescents, adults, or the elderly. These booster doses result in undesirable hypersensitivity reactions in the subject. Thus, in certain embodiments, the present invention provides a method for reducing the total number of booster doses required to provide protection against pathogen challenge in a subject. The method according to this aspect comprises administering a vaccine to a subject in a pharmaceutical composition comprising an IL-4R antagonist. The methods disclosed herein provide similar or better immune protection against pathogen challenge, even with reduced doses of vaccine. In certain embodiments, the present invention provides a method for administering IL-4R antagonists to subjects who are not administered IL-4R antagonists. In comparison, methods are provided that reduce the total number of vaccine doses by one or more doses, e.g., one dose, two doses, three doses or more. Administration of one dose of vaccine in combination with one or more doses of an IL-4R antagonist In another embodiment, administration of one or two doses of a vaccine in combination with one or more doses of an IL-4R antagonist is at least as effective as two doses of a vaccine not containing , which is at least as effective as three doses of a vaccine that does not contain an IL-4R antagonist. do.

[0044] The methods of the invention, according to certain embodiments, involve administering a vaccine to a subject, the vaccine comprising an IL-4R antagonist. As used herein, the expression "in combination with" refers to administration of a vaccine before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. The term "in combination with" also refers to administration of an IL-4R antagonist and and sequential or concomitant administration of vaccines.

[0045] For example, when administered "before" administration of a vaccine, the IL-4R antagonist In certain embodiments, the IL-4R antagonist may be administered about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week before administration of the vaccine. The pharmaceutical composition comprising an IL-4R antagonist may be administered 8 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before the vaccine. When administered "after" the vaccine, the pharmaceutical composition comprising the IL-4R antagonist may be administered 8 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before the vaccine. The IL-4R antagonist may be administered about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks after administration of the vaccine. In certain embodiments, the IL-4R antagonist is administered about 10 minutes, about 15 minutes, about 30 minutes, or about 15 minutes after administration of the vaccine. The IL-4R antagonist may be administered about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the vaccine. "Concurrent" or "concomitant" administration with the vaccine refers to the administration of the IL-4R antagonist at the same time as the vaccine. administered to the subject in a separate dosage form less than 10 minutes after (before, after, or at the same time as) administration of or as a single combined dosage formulation containing both the vaccine and the IL-4R antagonist. It is meant to be administered to elephants.

[0046] The present invention relates to a method for treating a disease by administering the above-mentioned vaccine in combination with an effective amount of a pharmaceutical composition containing an IL-4R antagonist. The present invention also includes a method for increasing the efficacy and / or safety of vaccines, comprising administering the pharmaceutical composition to a subject in need thereof using the pharmaceutical composition, for example, as part of a specific vaccination plan, to the subject in multiple doses.For example, the vaccination plan can include administering multiple doses of pharmaceutical composition to the subject about once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, once every 2 months, once every 3 months, once every 4 months, or less frequently, followed by administering one or more doses of vaccine to the subject.

[0047] In certain embodiments, each dose of the IL-4R antagonist is In certain embodiments, each dose of IL-4R antagonist contains 1 to 50 mg. contains 10-600 mg of IL-4R antagonist.

[0048] In a related embodiment, the present invention provides a method for administering one or more doses of an IL-4R antagonist. followed by administration of a dose of an IL-4R antagonist concurrently with the vaccine, optionally followed by Vaccination in a subject, comprising administering one or more doses of an IL-4R antagonist In certain embodiments, the vaccination regimen includes an IL-4R antagonist. 1 to 10 weekly doses of IL-4R antagonist administered concurrently with the vaccine. This involves administering a single dose of IL-4R antagonist to a patient, followed by 1 to 3 weekly doses of IL-4R antagonist. In embodiments, the vaccination regimen includes one or more booster doses of the vaccine. In further embodiments, each booster dose of the vaccine contains one or more IL-4R antagonists. Multiple doses are administered subsequently.

[0049] Methods for treating atopic dermatitis According to certain aspects, the present invention provides methods of treating atopic dermatitis (AD) in a patient without interfering with the patient's response to a vaccine. In certain embodiments, the present invention provides methods of treating AD in a patient without suppressing the patient's response to a vaccine. In certain embodiments, the present invention provides methods of treating AD in a patient susceptible to microbial infection and / or in need of a vaccine against an infectious disease. The method according to this aspect comprises administering an IL-4R antagonist to a subject in need thereof. In certain embodiments, the method comprises selecting a patient diagnosed with atopic dermatitis who has recently received or will receive a vaccine, and administering to the patient one or more doses of an IL-4R antagonist. wherein the IL-4R antagonist also reduces the patient's response to the vaccine. , nor attenuated. As used herein, the term "patient response to a vaccine" refers to a protective immune response to a vaccine in a patient. In the context of the present invention, the term refers to the level of antibodies produced in a patient with AD who has been treated or not with dupilumab. As used herein, the phrase "patient in need thereof" refers to a human animal that exhibits one or more symptoms or signs of atopic dermatitis and / or a human animal that has been diagnosed with atopic dermatitis. In certain embodiments, the methods of the present invention may be used to treat patients who exhibit elevated levels of one or more biomarkers associated with AD (e.g., IgE). Biomarkers associated with AD are described in U.S. Publication No. 20140072583, which is incorporated herein in its entirety. For example, the methods of the present invention may be used to treat patients who exhibit elevated levels of IgE or In the context of the present invention, a "patient in need thereof" is defined as, for example, a patient who has, prior to treatment, a clinically significant symptom such as elevated IGA, BSA, EASI, SCORAD, 5D-pruritus, and / or NRS scores. The term "subject in need thereof" may include patients who exhibit (or have exhibited) one or more AD-associated parameters and / or elevated levels of one or more AD-associated biomarkers, such as, for example, IgE and / or TARC. In certain embodiments, a "subject in need thereof" may include a subset of a population that may be susceptible to AD or exhibit elevated levels of AD-associated biomarkers. For example, a "subject in need thereof" may include a subset of a population defined by race or ethnicity present in the population.

[0050] In some embodiments, the method herein may be used to treat AD in children under 1 year old.For example, the method may be used to treat infants under 1 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.In other embodiments, the method may be used to treat children and / or adolescents under 18 years old.For example, the method may be used to treat children or adolescents under 17 years old, 16 years old, 15 years old, 14 years old, 13 years old, 12 years old, 11 years old, 10 years old, 9 years old, 8 years old, 7 years old, 6 years old, 5 years old, 4 years old, 3 years old, or 2 years old.In certain embodiments, the method may be used to treat AD in children who need vaccines against infectious diseases (e.g., whooping cough, diphtheria, tuberculosis, RSV, measles, mumps, and rubella).

[0051] In certain embodiments, a patient in need thereof is an adult with AD and over the age of 20 who may require a booster dose of the vaccine.

[0052] As used herein, "atopic dermatitis (AD)" refers to an inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and scaly and dry eczema lesions. The term "atopic dermatitis" includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergies (e.g., allergies to certain foods, pollen, mold, house dust mites, animals, etc.), radiation exposure, and / or asthma. The present invention encompasses methods of treating patients with mild, moderate to severe, or severe AD. As used herein, "moderate to severe AD" is characterized by extensive, extremely pruritic skin lesions that are often exacerbated by persistent bacterial, viral, or fungal infections. Moderate to severe AD also includes chronic AD in patients. In many cases, chronic lesions include thickened patches of skin, lichenification, and fibrous papules. Patients affected by moderate to severe AD also generally have more than 20% of the affected body skin, or 10% of the skin area, in addition to the improvement of eye, hand and body wrinkles.Moderate to severe AD is also considered to exist in patients who require frequent treatment with topical corticosteroids.Patients can also be described as having moderate to severe AD when they are resistant or unresponsive to the treatment with topical corticosteroids or calcineurin inhibitors or any other commonly used therapeutic agent known in the art.Patients with moderate to severe or severe AD can also show further aggravation or relapse of disease.

[0053] The present invention includes methods for treating AD in patients who are resistant, unresponsive, or inadequately responsive to treatment with topical corticosteroids (TCS) or calcineurin inhibitors. As used herein, the term "resistant, unresponsive, or inadequately responsive to TCS or calcineurin inhibitors" refers to a subject or patient with AD who has been treated with a TCS or calcineurin inhibitor, where the TCS / calcineurin inhibitor has no therapeutic effect. In some embodiments, the term refers to reduced patient compliance and / or toxicity and side effects and / or ineffectiveness of the TCS / calcineurin inhibitor administered to reduce, ameliorate, or alleviate symptoms of AD. In some embodiments, the term refers to patients with moderate to severe AD who are refractory to treatment with a TCS / calcineurin inhibitor. In some embodiments, the term refers to patients with uncontrolled AD despite treatment with a TCS and / or a calcineurin inhibitor. In some embodiments, patients who are "TCS or calcineurin inhibitor resistant, unresponsive, or inadequately responsive" may not show improvement in one or more parameters associated with AD. Examples of parameters associated with AD are described elsewhere herein. For example, treatment with a TCS / calcineurin inhibitor may not result in a decrease in pruritus or EASI or BSA scores. In some embodiments, the present invention includes methods for treating moderate to severe AD in patients who have been previously treated with a TCS / calcineurin inhibitor for one month or more and who do not show a decrease in one or more parameters associated with AD. For example, the method may be used to treat patients with chronic AD who are on a stable TCS / calcineurin inhibitor regimen and have a BSA score of 10% or higher or an IGA score of 3 or higher.

[0054] In certain embodiments, the present invention provides a method for administering an IL-4R antagonist to a patient in need thereof, comprising administering one or more provides a method for producing improvements in multiple AD-associated parameters. Examples of "AD-associated parameters" include (a) Investigator's Global Assessment (IGA); (b) Atopic Dermatitis Body Surface Area Lesion (BSA); (c) Eczema Area and Severity Index (EASI); (d) SCORAD; (e) 5-D Pruritus Scale; and (f) Pruritus Numerical Assessment Scale. Parameters associated with AD are described in U.S. Publication No. 20140072583, which is incorporated herein in its entirety. "Improvement in parameters associated with AD" includes IGA, BSA, EASI, SCORAD, 5-D pruritus scale, and the like. As used herein, the term "baseline" refers to a decrease from baseline in one or more of the AD-related parameters, such as the serotonin-releasing hormone (SHR), serotonin-releasing hormone (SHR), or NRS. As used herein, the term "baseline" refers to the value of the AD-related parameter for a subject prior to or at the time of administration of the pharmaceutical composition of the present invention.

[0055] To determine whether a parameter associated with AD has been "improved," the parameter is quantified at baseline and at one or more time points after administration of a pharmaceutical composition of the present invention. For example, parameters associated with AD may be measured at the end of, or at or after, the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 14th, 15th, 22nd, 25th, 29th, 36th, 43rd, 50th, 57th, 64th, 71st, 85th day; or the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th week after initial treatment with a pharmaceutical composition of the present invention. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (e.g., a decrease) in the parameter associated with AD.

[0056] Interleukin-4 receptor antagonist The methods of the present invention comprise administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist. As used herein, an "IL-4R antagonist" (also referred to herein as an "IL-4R inhibitor," "IL-4Rα antagonist ... An IL-4 receptor (also referred to as an "IL-4R antagonist," "IL-4R blocker," "IL-4Rα blocker," etc.) is any agent that binds to or interacts with IL-4Rα or an IL-4R ligand, and any agent that inhibits or attenuates the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 13. Type 1 IL-4 receptors include the IL-4Rα chain and the γc chain. It is a dimeric receptor. Type 2 IL-4 receptor consists of the IL-4Rα chain and the IL-13Rα1 chain. The type 1 IL-4 receptor interacts with and is stimulated by IL-4, whereas the type 2 IL-4 receptor interacts with and stimulates both IL-4 and IL-13. Therefore, the IL-4R antagonists that can be used in the methods of the present invention The IL-4R antagonists of the present invention may function by blocking signaling mediated by IL-4, signaling mediated by IL-13, or signaling mediated by both IL-4 and IL-13. The interaction of IL-4 and / or IL-13 with the type 2 receptor may be prevented.

[0057] Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor bodies" (e.g., engineered receptor bodies containing the ligand-binding domain of an IL-4R component), and and an antibody or an antigen-binding fragment of an antibody that specifically binds to human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0058] Anti-IL-4Rα antibodies and antigen-binding fragments thereof According to certain exemplary embodiments of the present invention, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. As used herein, the term "antibody" includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains connected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (herein referred to as HCVR or VV). H The heavy chain constant region is divided into three domains: , C H 1. C H 2 and C H 3. Each light chain comprises a light chain variable region (LCV) R or V L The light chain constant region comprises one domain, (C L 1) V H and V L The regions are called framework regions (FR). Interspersed with conserved regions, they can be further divided into regions of hypervariability called complementarity-determining regions (CDRs). H and V L consists of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In a different embodiment of the invention, an anti-IL- The FRs of a 4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a comparative analysis of two or more CDRs.

[0059] As used herein, the term "antibody" also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically derived, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies may be derived, for example, from intact antibody molecules using any suitable standard technique, such as proteolytic digestion, or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries). The DNA can be prepared or synthesized. The DNA can be sequenced and manipulated using chemical or molecular biological techniques, for example, to arrange one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add or delete amino acids.

[0060] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v (vi) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking a hypervariable region of an antibody (e.g., an isolated complementarity-determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment" as used herein.

[0061] An antigen-binding fragment of an antibody will typically contain at least one variable domain, which may be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in-frame with one or more framework sequences. L Domain and associated V H In an antigen-binding fragment having a domain, V H and V L The domains may be positioned relative to each other in any suitable configuration. For example, the variable region may be a dimer, with V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may contain a dimer of monomeric V H or V L It may contain domains.

[0062] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary arrangements of variable and constant domains that may be found in an antigen-binding fragment of an antibody of the invention include: (i) V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1- C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)VL -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L Variable and constant domains, including any of the typical configurations listed above. In any configuration, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that provide a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present invention may be linked to each other and / or to one or more monomeric V H Also is V L The above-listed domains in non-covalent association (e.g., via disulfide bonds) The antibody may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain arrangements provided.

[0063] As used herein, the term "antibody" also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies will typically contain at least two different variable domains, where each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format may be adapted for use in the context of the antibodies or antigen-binding fragments of antibodies of the present invention using routine techniques available in the art. For example, the present invention provides antibodies in which one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof. The present invention also includes methods involving the use of bispecific antibodies, where the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present invention include, for example, scFv-based or antibody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knob-into-hole, common light chain (e.g., common light chain with knob-into-hole), CrossMab, CrossFab, (SEED)body, leucine zipper, duobody, IgG1 / IgG2, dual acting Fab (DAF), and the like. )-IgG, and Mab 2 including, but not limited to, bispecific formats (for reviews of the aforementioned formats, see, e.g., Klein et al. 2012, mAbs 4:6, 1-11, and the references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugates, for example, where unnatural amino acids with orthogonal chemical reactivity are used to create site-specific antibody-oligonucleotide conjugates, which are then , which self-assemble into multimeric complexes with defined composition, valence, and geometry (see, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).

[0064] The antibody used in the method of the present invention may be a human antibody. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibody of the present invention may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations induced by in vitro random or site-specific mutagenesis or in vivo somatic mutation), for example, in the CDRs and in particular in the CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0065] The antibody used in the methods of the present invention may be a recombinant human antibody. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector introduced into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created, or isolated by any other means, including splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis), which results in the V H oh Yobi V L The amino acid sequence of the region is human germline V H and VL While derived from and related to sequences, These are sequences that cannot naturally occur within the human antibody germline repertoire in vivo.

[0066] According to certain embodiments, the antibodies used in the methods of the present invention are directed to IL-4Rα. Specifically binds. The term "specifically binds" and the like means that an antibody or an antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-4Rα, as used in the context of the present invention, can be determined by a surface plasmon resonance assay. less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, less than about 0.1 nM, or less than about 0.05 nM, as measured at D However, the present invention also includes an isolated antibody that specifically binds to human IL-4Rα or a portion thereof. has cross-reactivity with other antigens, such as IL-4Rα molecules from other (non-human) species. Good too.

[0067] According to certain exemplary embodiments of the present invention, the IL-4R antagonist comprises a heavy chain variable Complementarity comprising any of the amino acid sequences of the anti-IL-4R antibodies described in U.S. Pat. No. 7,608,693, the light chain variable region (HCVR), the light chain variable region (LCVR), and / or the anti-IL-4R antibodies described in U.S. Pat. No. 7,608,693. an anti-IL-4Rα antibody, or an antigen-binding fragment thereof, comprising the CDRs thereof; In certain exemplary embodiments, an anti-IL-4Rα antibody or antigen-binding fragment thereof that can be used in the context of the methods of the present invention has the amino acid sequence of SEQ ID NO:1. and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. According to certain embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof comprises: The anti-IL-4R antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises The agent comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2. According to certain exemplary embodiments, the methods of the invention comprise an anti-IL-4 antibody comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence of SEQ ID NOs: 3-4-5-6-7-8. In certain embodiments, the methods of the present invention involve the use of an anti-IL-4R antibody (referred to as "dupilumab" and known in the art), or a biological equivalent thereof. In certain embodiments, the methods of the present invention involve the use of an anti-IL-4R antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9. In some embodiments, the anti-IL-4R antibody comprises the amino acid sequence of SEQ ID NO: 10. An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 is the fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present invention involve the use of dupilumab, or a biological equivalent thereof. As used herein, the term "bioequivalent" refers to an anti-IL-4R antibody or IL-4R binding protein or fragment thereof that is a pharmaceutical equivalent or pharmaceutical substitute whose rate and / or degree of absorption is not significantly different from that of dupilumab when administered in single or multiple doses at the same molar dose under similar experimental conditions. In the context of the present invention, the term ... not clinically meaningfully different from dupilumab in their safety, purity, and / or efficacy. It refers to an antigen-binding protein that binds to the target antigen.

[0068] In certain specific embodiments, the methods of the present invention provide an anti-mouse anti-IL-4R antibody or its antigen-binding fragment comprising the HCVR sequence of SEQ ID NO: 11 and the LCVR sequence of SEQ ID NO: 12. In an exemplary embodiment, the methods of the invention involve the use of an anti-mouse anti-IL-4R antibody in increasing the efficacy and / or safety of a pertussis vaccine in a Bordetella pertussis aerosol-challenged mouse model.

[0069] In certain specific embodiments, the methods of the present invention provide an anti-monkey anti-IL-4R antibody or its antigen-binding fragment comprising the HCVR sequence of SEQ ID NO: 14 and the LCVR sequence of SEQ ID NO: 15. In an exemplary embodiment, the methods of the invention involve the use of anti-monkey anti-IL-4R antibodies in increasing the efficacy and / or safety of a pertussis vaccine in a clinically relevant infant baboon model.

[0070] Other anti-IL-4Rα antibodies that can be used in the context of the methods of the present invention include, for example, , an antibody known in the art (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or U.S. Patent No. 7,186 any of the anti-IL-4Rα antibodies described in U.S. Pat. No. 7,605,237, U.S. Pat. No. 7,608,693, or U.S. Pat. No. 8,092,804 Includes.

[0071] The anti-IL-4Rα antibodies used in the context of the methods of the present invention have pH-dependent binding characteristics. For example, the anti-IL-4Rα antibody for use in the methods of the present invention may have a neutral Alternatively, the antibody may exhibit reduced binding to IL-4Rα at acidic pH compared to normal pH. The anti-IL-4Rα antibodies of the present invention have enhanced binding to their antigens at acidic pH compared to neutral pH. The term "acidic pH" may refer to a bond formed by a cleavage or cleavage. The term "acidic pH" includes pH values ​​less than about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or less. As used herein, the term "neutral pH" refers to a pH of about 7.0 to about 7.4. The term "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0072] In certain cases, "reduced activity of IL-4R at acidic pH compared to neutral pH" "Binding" refers to the K of antibody binding to IL-4Rα at neutral pH. D IL- at acidic pH K of antibody binding to 4Rα D It is expressed in terms of the ratio of values ​​(or vice versa). For example, an antibody or or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof is D For purposes of the present invention, a ratio of about 3.0 or greater is considered to be "relative to neutral pH" These may be considered to exhibit "reduced binding to IL-4Rα at acidic pH." In a typical embodiment, the acidic / neutral K for an antibody or antigen-binding fragment of the invention D The ratios are approximately 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7 It can be 0.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or more.

[0073] Antibodies with pH-dependent binding characteristics may be obtained by screening a population of antibodies for reduced (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. In addition, modification of the antigen-binding domain at the amino acid level may result in antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues, antibodies with reduced antigen binding at acidic pH compared to neutral pH may be obtained. As used herein, the expression "acidic pH" refers to pH 6.0 or less.

[0074] Pharmaceutical Composition The present invention includes methods comprising administering to a patient an IL-4R antagonist, wherein The IL-4R antagonist is contained in the pharmaceutical composition. The excipients are formulated with suitable carriers, excipients, and other agents to provide for appropriate delivery, tolerance, etc. Many suitable formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, a formulary known to all pharmacists. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions of carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[0075] The dose of the antibody administered to a patient according to the method of the present invention may vary depending on the age and size of the patient, symptoms, condition, route of administration, etc. The dose is typically determined based on body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. The effective dosage and schedule for administering a pharmaceutical composition containing an anti-IL-4R antibody are The schedule may be empirically determined; for example, patient progress can be monitored by periodic evaluation, and dosages can be adjusted accordingly. Furthermore, interspecies adjustments of dosages can be made using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Specific exemplary dosages of anti-IL4R antibodies and dosing regimens, including those that can be used in the context of the present invention, are disclosed elsewhere herein.

[0076] A variety of delivery systems are known and can be used to administer IL-4R antagonists, including Pharmaceutical compositions can be administered, e.g., encapsulated in liposomes, microparticles, microcapsules, mutant viruses, recombinant cells capable of expressing receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). (See references). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous layers (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other biologically active agents.

[0077] The pharmaceutical compositions of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, for subcutaneous delivery, a pen delivery device is easily adapted to deliver the pharmaceutical compositions of the present invention. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there is no replaceable cartridge. Rather, disposable pen delivery devices are pre-filled with the pharmaceutical composition held in a container within the device. Once the container is emptied of the pharmaceutical composition, the entire device is discarded.

[0078] A number of reusable pen and self-injection delivery devices have application in the subcutaneous delivery of the pharmaceutical compositions of the present invention. Examples include the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic), to name just a few. Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ Pen, HUMALOG™ Pen, HUMALIN 70 / 30™ Pen (Eli Lilly and Company, Indianapolis, Indiana), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ Pen (Becton Dickinson, Franklin Lakes, New Jersey), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen delivery devices suitable for subcutaneous delivery of the pharmaceutical compositions of the present invention include the SOLOSTAR™ Pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ Pen (Abbott Laboratories), to name just a few. Leeds, Abbott Park, Illinois).

[0079] In certain situations, pharmaceutical compositions can be delivered in controlled-release systems. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled-release system is placed near the target of the composition, thereby requiring only a fraction of the systemic dose (see, for example, Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled-release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0080] Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, drip infusions, and the like. These injectable preparations may be prepared by known methods. For example, injectable preparations may be prepared by dissolving, suspending, or emulsifying the above-described antibody or its salt in a sterile aqueous or oily medium commonly used for injections. Aqueous media for injection include, for example, isotonic solutions containing physiological saline, glucose, and an adjuvant, which may be an aqueous medium containing, for example, an alcohol (e.g., ethanol), a polyhydric alcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant (e.g., polysorbate 80, HCO-50 (hardened hCO-1), or the like. The injection may be used in combination with a suitable solubilizer such as a polyoxyethylene (50 mol) adduct of corn oil. As the oil medium, for example, sesame oil, soybean oil, etc. may be used, which may be used in combination with a solubilizer such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared can be filled into a suitable ampule.

[0081] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in dosage forms with unit doses corresponding to the dose of the active ingredient. Such dosage forms with unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0082] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present invention Products are disclosed, for example, in US Pat. No. 8,945,559.

[0083] Vaccine Composition In certain embodiments, the present invention provides a vaccine composition comprising a vaccine adjuvant, wherein the vaccine adjuvant comprises an IL-4R antagonist. As used herein, the term "adjuvant" refers to any substance that, when used in combination with a specific vaccine antigen, acts to accelerate, prolong, or enhance an antigen-specific immune response. In the context of the present invention, an adjuvant (e.g., IL-4R antagonist) compared with those receiving a vaccine that does not contain an IL-4R antagonist. In certain embodiments, the use of IL-4R antagonists can be used to treat, for example, allergies to vaccine components. In certain embodiments, the use of an IL-4R antagonist as an adjuvant increases the safety of the administered vaccine by reducing the risk of an IL-4R reaction. For example, administration of one dose of a vaccine composition with an adjuvant (i.e., an IL-4R antagonist) according to the present invention can reduce the total number of doses of vaccine administered. Administration of one or two doses of a vaccine according to the present invention with an adjuvant according to the present invention is as effective as administration of two doses of a vaccine without an adjuvant according to the present invention. Similarly, administration of one or two doses of a vaccine according to the present invention with an adjuvant according to the present invention is as effective as administration of three doses of a vaccine without an adjuvant according to the present invention. In certain embodiments, the vaccine composition includes a second adjuvant (e.g., alum).

[0084] In certain embodiments, the IL-4R antagonist is an IL-4R antagonist described herein. and an anti-IL-4R antibody or antigen-binding fragment thereof. wherein the anti-IL-4R antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof is , comprising three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0085] Immunogens or antigens suitable for use in the vaccine compositions of the invention may be selected from the group consisting of inactivated pathogens, attenuated pathogens, immunogenic subunits (e.g., proteins, polypeptides, peptides, epitopes, haptens), or recombinant expression vectors comprising a plasmid with an immunogenic insert. In one embodiment of the invention, the immunogen is an inactivated or killed microorganism. In certain embodiments, the vaccine composition is directed against Bordetella pertussis, Corynebacterium diptheriae, Clostridium tetani, Mycobacterium tuberculosis, Plasmodium spp., Bacillus anthracis, Vibrio cholerae, Salmonella typhi, Borrelia spp., Streptococcus pneumoniae, S. cerevisia ... The vaccine composition comprises a component derived from a microorganism selected from the group consisting of Taphylococcus aureus, Escherichia coli, Clostridium spp., Mycobacterium leprae, Yersinia pestis, influenza virus, varicella-zoster virus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), poliovirus, smallpox virus, rabies virus, rotavirus, human papillomavirus, Ebola virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, lyssavirus, measles virus, mumps virus, and rubella virus. In certain embodiments, the vaccine composition comprises a vaccine component selected from the group consisting of tetanus toxoid, diphtheria toxoid, inactivated pertussis toxin, filamentous hemagglutinin, pertactin, type 2 fimbriae, type 3 fimbriae, and formalin-inactivated respiratory syncytial virus.

[0086] The vaccine composition of the present invention comprises at least one pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to a carrier that can be administered to a patient together with an antigen, does not destroy its pharmacological activity, and is nontoxic when administered in a dose sufficient to deliver a pharmaceutically effective amount of the compound. Useful pharmaceutically acceptable vehicles or excipients are standard. Remington's Pharmaceutical Sciences by E.W. Martin, Mack Publishing Co., Easton, Pa., 15th Edition (1975) describes compositions and formulations suitable for pharmaceutical delivery of vaccines. In general, the nature of the vehicle or excipient will depend on the particular mode of administration employed. For example, parenteral formulations usually contain a pharmaceutically and physiologically acceptable injectable liquid as a vehicle, such as water, physiological saline, balanced salt solution, aqueous dextrose, glycerol, or the like. For solid compositions (e.g., lyophilized lozenge, powder, pill, tablet, or capsule forms), conventional non-toxic solid vehicles or excipients may include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral vehicles or excipients, the immunogen composition to be administered may contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, pH buffering agents, and the like, for example, sodium acetate or sorbitan monolaurate.

[0087] As will be appreciated by those skilled in the art, vaccines are appropriately formulated to be compatible with the intended route of administration. Examples of suitable routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, intraperitoneal, oral (e.g., buccal, inhalation, nasal and pulmonary spray), intradermal, transdermal (topical), transmucosal, and intraocular administration.

[0088] Dosage regimen The methods of the invention, according to certain embodiments, involve administering a vaccine to a subject, the vaccine comprising an IL-4R antagonist. As used herein, the term "anti-IL-4R antibody" includes administering the same in combination with an IL-4R antibody (e.g., an anti-IL-4R antibody). The expression "in conjunction with" refers to the use of a vaccine before, after, or after the administration of an IL-4R antagonist. The term "in combination with" also refers to administration of an IL-4R antagonist. This includes sequential or simultaneous administration of a test and a vaccine.

[0089] For example, when administered "before" an IL-4R antagonist, the vaccine may be administered less than 72 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the IL-4R antagonist. When administered "after" the IL-4R antagonist, the vaccine It may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than about 72 hours later. Administration of the vaccine occurs within less than 5 minutes of (before, after, or after the administration of) the IL-4R antagonist. The vaccine and the IL-4R antagonist may be administered to the subject in separate dosage forms at the same time, or the vaccine and the IL-4R antagonist may be administered together. By this means, the therapeutic agent is administered to a subject as a single combined dosage formulation containing both the active ingredient and the agonist.

[0090] The present invention provides a method for administering an IL-4R antagonist to a subject for up to one week, as long as a therapeutic response is achieved. The present invention also includes methods comprising administering an anti-IL-4R antibody at a dosing frequency of about 4 times, twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently. In certain embodiments, once-weekly dosing in amounts of about 25 mg, 50 mg, 150 mg, or 300 mg may be utilized.

[0091] According to certain embodiments of the present invention, multiple doses of an IL-4R antagonist are administered to a subject. The method according to this aspect of the invention comprises administering to the subject multiple doses of the IL-4R antagonist sequentially. "Sequential administration" refers to administration of each dose of an IL-4R antagonist to a subject at different points in time. The present invention relates to the administration of IL-4R antagonists to a patient, for example, on different days separated by a predetermined interval (e.g., several hours, days, weeks, or months). one initial dose of an IL-4R antagonist, followed by one or more secondary doses of an IL-4R antagonist; and optionally followed by a series of one or more tertiary doses of an IL-4R antagonist. The method includes administering.

[0092] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the administration of an IL-4R antagonist. The term "initial dose" refers to the time sequence of administration of the IL-4R antagonist. Thus, an "initial dose" is the dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); a "secondary dose" is the dose administered after the initial dose; and a "tertiary dose" is the dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist. However, in certain embodiments, the IL-4R antagonist contained in the initial, secondary and / or tertiary doses may be administered in a frequency that is generally different from one another. The amounts of the compounds may be varied relative to one another during the course of treatment (e.g., upward or downward as needed). In certain embodiments, the initial dose comprises a first amount of the antibody or antigen-binding fragment thereof, and one or more secondary doses each comprise a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or antigen-binding fragment thereof is 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x the second amount of the antibody or antigen-binding fragment thereof. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered as a "loading dose" at the beginning of the treatment regimen, followed by subsequent doses (e.g., "maintenance doses") that are administered less frequently. For example, an IL-4R antagonist may be administered to a patient in need thereof. A loading dose of about 300 mg to about 600 mg may be administered, followed by one or more maintenance doses of about 25 mg to about 300 mg. According to one embodiment, the starting dose and one or more secondary doses each contain 10 mg to 600 mg of the IL-4R antagonist, e.g. , 100 mg to 400 mg of an IL-4R antagonist, for example, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg or 500 mg of an IL-4R antagonist.

[0093] In one exemplary embodiment of the invention, each secondary and / or tertiary dose is administered 1 to 14 (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2, or more) weeks after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" refers to the amount of IL-4R antagonist administered to a patient prior to the administration of the immediately following dose in the series with no intervening doses in a multiple administration sequence. means the dose.

[0094] The method according to this aspect of the invention comprises administering to the patient a secondary and / or secondary dose of an IL-4R antagonist. may include administering any total number of tertiary doses. For example, in certain embodiments, only one secondary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to a patient. Similarly, in certain embodiments, only one tertiary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to a patient.

[0095] In embodiments comprising multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to a patient 1 to 6 weeks after the immediately preceding dose. Similarly, in embodiments comprising multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to a patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to a patient can vary over the course of the dosing regimen.

[0096] Dosage The IL-4R antagonist ( The amount of the antibody (e.g., anti-IL-4R antibody) is generally an immunologically effective amount. As used, the phrase "immunologically effective amount" means the amount of IL-4R antagonist that causes an increase in the effectiveness of the vaccine or an enhanced or increased immune response to the vaccine. In the context of the present invention, the phrase "immunologically effective amount" refers to an amount of IL-4R antagonist that results in one or more of: (a) faster clearance of microbial pathogens from an infected host; (b) a reduction in vaccine-induced IgE levels; (c) an increase in Th1-type antigen-specific IgG; (d) a reduction in Th2-type antigen-specific IgG levels; (e) a reduction in the total number of vaccine doses; and / or (f) better protection against pathogen challenge and delay in infection upon pathogen challenge. In certain embodiments, The term "immunologically effective amount" refers to a prophylactically or therapeutically effective amount of an IL-4R antagonist. "An effective amount" includes an effective amount, which means the amount required for an effective immune response to prevent, treat, or alleviate a symptom or sign of an infectious disease. In certain embodiments, the phrase "immunologically effective amount" refers to the amount of an IL-4R antagonist that results in a detectable improvement in one or more symptoms or signs in a patient with atopic dermatitis, asthma, nasal polyposis, chronic sinusitis, eosinophilic esophagitis, or allergies. .

[0097] In the case of an anti-IL-4R antibody, an immunologically effective amount is about 0.05 mg to about 600 mg of an anti-IL-4R antibody, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about In certain embodiments, the amount of anti-IL-4R antibody can be 10 mg, 25 mg, 50 mg, 75 mg, 150 mg, or 600 mg. 300 mg will be administered to the subject.

[0098] The amount of IL-4R antagonist contained in each dose is 100 mg / kg of subject body weight. For example, the IL-4R antagonist may be administered to a subject at a dose of about 0.0001 to about 100 mg / kg of subject body weight. It may be administered at a dose of 1 g. [Example]

[0099] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmosphere.

[0100] Example 1: Administration of anti-IL-4R antibody suppresses serum total IgE induced by pertussis vaccine intentionally reduce In this example, the effect of anti-IL-4R antibodies on total serum IgE levels induced by whole-cell pertussis (wP) or acellular pertussis (aP) vaccines was investigated using Bordetella pertussis vaccines. The efficacy of the tetanus vaccine was evaluated using a Tachys aerosol challenge infection model. Tetanus and wP and aP vaccines are known in the art to induce a log-scale boost in IgE in some patients. Table 1 lists the components of the aP and wP vaccines used in the examples herein.

[0101] [Table 1]

[0102] C57BL / 6 mice were immunized with either TDaP [Adacel® (Sanofi Pasteur)] or DTP vaccine (Serum Institute of India, Pune, India) on days -42 and -14 prior to aerosol challenge (day 0) with a virulent strain of Bordetella pertussis. Treatment with anti-mouse IL-4R antibody ("anti-IL-4Rα") or an isotype control antibody began 1 week before the first immunization and continued weekly until day 7. The treatment regimen is summarized in Figure 1. The anti-IL-4Rα antibody used in this example was identified as SEQ ID NO: 11 and an LCVR having an amino acid sequence comprising SEQ ID NO: 12.

[0103] Serum was collected from naive and immunized mice (12 mice per group) on day 0. Total IgE levels were analyzed by ELISA. Total serum IgE levels were determined by ELISA using biotin-conjugated anti-mouse IgE antibody and peroxidase-conjugated streptavidin. Antibody levels are expressed as total IgE (μg / mL) determined from a standard curve.

[0104] Treatment of mice with anti-IL-4Rα resulted in significantly increased IL-4 expression compared to mice treated with an isotype control antibody. This significantly reduced total serum IgE levels in mice immunized with the TDaP (aP) and DTP (wP) vaccines (Figure 2). The reduction in serum IgE indicates a vaccine-induced reduction in Th2 responses and / or prevention or reduction in allergic reactions.

[0105] Example 2: Effect of anti-IL-4R antibody treatment on antigen-specific serum IgG antibodies in mice vaccinated with pertussis vaccine In this example, the effect of whole cell pertussis (wP; Th1 immune response) or acellular pertussis (aP; Th2 immune response) vaccines on antigen-specific serum antibodies against IL-4 The efficacy of R antibodies was evaluated using a Bordetella pertussis aerosol challenge infection model. C57BL / 6 mice were immunized with either acellular pertussis (aP) vaccine [Adacel® TDaP (Sanofi Pasteur)] or whole cell pertussis (wP) (DTP, Serum Institute of India, Pune, India) on days -42 and -14 prior to aerosol challenge (day 0) with a virulent strain of Bordetella pertussis. Treatment with anti-mouse IL-4R antibody ("anti-IL-4Rα") or an isotype control antibody was performed after the initial immunization. The treatment regimen was started one week before the start of the study and continued once a week until day 7. The treatment regimen is summarized in Figure 1. The anti-IL-4Rα antibody used in this example was HIL-4Rα, which has the amino acid sequence of SEQ ID NO: 11. Anti-mouse IL-4 comprising a CVR and an LCVR having an amino acid sequence comprising SEQ ID NO: 12 Antigen-specific serum antibodies were analyzed by ELISA using plate-bound, heat-killed Bordetella pertussis or FHA (5 mg / mL). Bound antibodies were detected using biotin-conjugated anti-mouse IgG, IgG1, IgG2a, or IgG2c antibodies and peroxidase-conjugated streptavidin. Antibody levels are expressed as mean endpoint titers determined by extrapolation of the linear portion of the titration curve to 2 SD above the background value obtained with non-immunized mouse serum.

[0106] Serum IgG specific to heat-killed Bordetella pertussis was analyzed in mice treated with wP, while serum IgG specific to filamentous hemagglutinin (FHA) was analyzed in mice treated with aP. Immunization with aP or wP induced Bordetella pertussis-specific IgG; total IgG titers were significantly higher in mice immunized with aP than in mice immunized with anti-IL-4R. A very small (although significant) increase in antigen-specific total IgG was observed in mice immunized with wP, which was unchanged by treatment with α (Fig. 3). Immunization with aP induced primarily IgG1 anti-FHA antibodies (indicating a Th2-specific response), whereas anti-IL-4Rα treatment induced a significant increase in antigen-specific total IgG (Fig. 3). FHA-specific IgG2a and IgG2c titers (indicative of a Th1 response) were significantly enhanced by treatment with anti-IL-4Rα; titers were determined by isotype aP-immunized mice treated with anti-IL-4Rα showed significantly higher IL-4Rα expression levels than aP-immunized mice treated with a control antibody. The titers of heat-killed Bordetella pertussis (HK-BP)-specific IgG1 antibodies were significantly higher in the immunized mice (Figs. 5 and 6). There was no difference, but a slight significant increase in HK-BP-specific IgG2a and IgG2c titers in the group treated with anti-IL4Rα compared to the isotype control antibody. This increase in IgG2a and IgG2c titers was not significant for individual experiments (each consisting of 4 mice per group), but was significant when the results of multiple experiments were pooled.

[0107] Therefore, anti-IL-4Rα treatment inhibits the Th2 This was reflected in a switch from serum IgG1 to IgG2a / c antibodies and a drop in IgE concentrations.

[0108] Example 3: Effect of anti-IL-4R antibodies on antigen-specific production of cytokines In this example, the effect of anti-IL-4R antibodies on antigen-specific cytokine production after ex vivo restimulation of splenocytes was investigated using a Bordetella pertussis aerosol challenge infection model. C57BL / 6 mice were immunized with either acellular pertussis (aP) vaccine [Adacel® TDaP (Sanofi Pasteur)] or whole cell pertussis (wP) (DTP, Serum Institute of India, Pune, India) on days -42 and -14 prior to aerosol challenge (day 0) with a virulent strain of Bordetella pertussis. Treatment with anti-mouse IL-4R antibody ("anti-IL-4Rα") or isotype control antibody began 1 week before the first immunization and continued weekly until day 7. The treatment regimen is summarized in Figure 1. The anti-IL-4Rα antibody used in this example was the amino acid sequence of SEQ ID NO: 11. The anti-mouse IL-4R antibody contained an HCVR having the amino acid sequence of SEQ ID NO: 12 and an LCVR having the amino acid sequence of SEQ ID NO: 13. The serum was collected from naive mice and immunized mice (1 Mice were collected from each group (four mice per group per experiment) on the day of challenge (day 0). Antigen-specific cytokine production by splenocytes was analyzed by ELISA. Splenocytes were prepared from the spleens of mice by mechanical disruption of splenic tissue. Splenocytes were cultured with the indicated number or concentration of heat-killed Bordetella pertussis or purified FHA. Supernatants were removed after 72 hours and analyzed for IL- 13, IL-17 and IFNγ concentrations were determined by ELISA.

[0109] Spleen cells from aP-immunized mice treated with anti-IL-4Rα were compared with those treated with an isotype control. In response to FHA stimulation, mice treated with anti-IL-4Rα produced significantly higher interferon-gamma (IFNγ) levels in a dose-dependent manner than mice treated with anti-IL-4Rα (Figure 7). IFNγ levels were detected in splenocytes from all anti-IL-4Rα-treated mice, but were lower in one of four aP-immunized mice treated with the isotype control. There was a trend towards reduced IL-13 in splenocytes from treated aP-immunized mice ( (Data not shown). FHA-specific IL-17 was not detected. Bordetella pertussis-specific IL-17 and IFNγ by splenocytes from immunized mice Production was similar across all immunization groups (data not shown).

[0110] Example 4: Treatment with anti-IL-4R antibodies enhances the efficacy of pertussis vaccines In this example, the protective efficacy of anti-IL-4R antibodies as adjuvants for whole-cell pertussis (wP) or acellular pertussis (aP) vaccines was evaluated in Bordetella pertussis strains. An aerosol challenge infection model was evaluated. C57BL / 6 mice were immunized with either acellular pertussis (aP) vaccine [Adacel® TDaP (Sanofi Pasteur)] or whole cell pertussis (wP) (DTP, Serum Institute of India, Pune, India) on days -42 and -14 prior to aerosol challenge (day 0) with a virulent strain of Bordetella pertussis. Treatment with anti-mouse IL-4R antibody ("anti-IL-4Rα") or an isotype control antibody began 1 week before the first immunization and continued weekly until day 7. The treatment regimen is summarized in Figure 1. The anti-IL-4Rα antibody used in this example is SEQ ID NO: The antibody was an anti-mouse IL-4R antibody comprising an HCVR having an amino acid sequence of SEQ ID NO: 11 and an LCVR having an amino acid sequence comprising SEQ ID NO: 12.

[0111] Colony-forming unit (CFU) levels per lung were assessed 0, 3, 7, 10, and 14 days after Bordetella pertussis challenge. Briefly, CFU counts were performed in lungs from groups of four mice at multiple intervals after challenge, following the course of infection. Lungs were aseptically removed and homogenized in 1 mL of sterile saline on ice. Undiluted and serially diluted homogenates from individual lungs were spotted in triplicate onto Bordet-Jung agar plates, and CFU numbers were calculated after 5 days of incubation. The limit of detection was approximately 0.3 log per lung for groups of four mice at each time point. 10 It was CFU.

[0112] Immunization with the wP vaccine conferred the highest level of protection against aerosol challenge with live Bordetella pertussis (Figure 8). Anti-IL-4Rα treatment in wP-immunized mice , similar to wP-immunized mice treated with isotype control, cleared the infection. 4Rα treatment significantly enhanced the efficacy of the aP vaccine; mice immunized with the aP vaccine and treated with anti-IL-4α had significantly higher IL-4α responses at day 3 compared to mice treated with the isotype control. Anti-IL-4Rα treatment significantly improved the efficacy of the aP vaccine. The efficacy was increased by one-third based on the area under the clearance curve. The results of this example demonstrate that IL-4R blockade is generally useful for enhancing the protective effect of vaccines that induce Th2 responses. This suggests that this is a promising treatment strategy.

[0113] Example 5: Administration of anti-IL-4R antibodies enhances the efficacy of a single dose of vaccine In this example, a Bordetella pertussis aerosol challenge infection model was used to evaluate the effect of anti-IL-4R antibodies on the efficacy of a single dose of vaccine.

[0114] C57BL / 6 mice were immunized once with either the aP vaccine (Adacel® TDaP; Sanofi Pasteur) or the wP vaccine (DTP, Serum Institute of India, Pune, India) 3 weeks before aerosol challenge with a virulent strain of Bordetella pertussis. Treatment with the control antibody began one week before immunization and continued weekly for the duration of the study. The treatment regimen is summarized in Figure 9. The anti-IL-4Rα antibody used in this example was The antibody contained an HCVR having the amino acid sequence of SEQ ID NO: 11 and an LCVR having the amino acid sequence containing SEQ ID NO: 12.

[0115] Mice were then challenged with Bordetella pertussis; lung CFUs were assessed at days 0, 3, 7, 14, and 21 post-infection. Briefly, CFU counts were performed in lungs from groups of four mice at multiple intervals post-challenge, following the course of infection. Lungs were aseptically removed and homogenized in 1 mL of sterile saline on ice. Undiluted and serially diluted homogenates from individual lungs were spotted in triplicate onto Bordet-Jung agar plates, and the number of CFUs was calculated after 5 days of incubation. The limit of detection was approximately 0.3 log per lung for groups of four mice at each time point. 10 It was CFU.

[0116] Immunization with the wP vaccine conferred the highest level of protection against aerosol challenge with live Bordetella pertussis (Figure 10), and the efficacy of the wP vaccine was comparable to that of anti-IL-4Rα treatment. Anti-IL-4Rα treatment did not change the IL-4Rα response even when the vaccine was reduced to a single dose. Immunization with aP and treatment with anti-IL-4α significantly enhanced the efficacy of the aP vaccine. Mice cleared bacterial infection by day 14, whereas mice immunized with aP and treated with isotype control still had a 4 log 10 The infection was not completely eliminated by day 21. Anti-IL-4Rα treatment significantly improved the efficacy of the aP vaccine. , increased by a factor of three based on the area under the clearance curve.

[0117] Anti-IL-4Rα completely eliminated Bordetella pertussis infection by day 14. The single-dose immunization protocol clearly illustrates the increased efficacy of the aP vaccine in combination with anti-IL4Rα treatment.

[0118] Example 6: Effect of low doses of anti-IL-4R antibodies on Th1 responses to acellular pertussis vaccine Fruit In this example, the effect of anti-IL-4R antibodies on serum total and antigen-specific antibodies induced by aP vaccine is evaluated in a mouse model (as performed herein). (Described in Examples 1-5). C57BL / 6 mice are immunized with an acellular pertussis (aP) vaccine [Adacel® TDaP (Sanofi Pasteur)]. Mice are treated with an anti-mouse IL-4R antibody ("anti-IL-4Rα") or an isotype control antibody (see below) prior to the first immunization. The anti-IL-4Rα antibody used in this example is It is an anti-mouse IL-4R antibody comprising an HCVR having the amino acid sequence of SEQ ID NO: 11 and an LCVR having the amino acid sequence comprising SEQ ID NO: 12.

[0119] In the first experiment, 1 to 5 doses of anti-IL-4R antibody were administered to different mice before vaccination with aP. Animals in different groups will be administered 25 mg / kg of mouse body weight. Animals in one group will also be administered anti-IL-4R antibody at the same time as the aP vaccine. Animals in one group will also be administered a pre-vaccination Four weeks after the prime dose, a further booster dose of aP vaccine is administered.

[0120] In another experiment, 1 to 5 doses of anti-IL-4R antibody were administered at different doses before vaccination with aP. Animals in each group will be administered 10 mg / kg of mouse body weight. Animals in one group will also be administered anti-IL-4R antibody at the same time as the aP vaccine. Animals in one group will also be administered a priming Four weeks after the dose, a further booster dose of aP vaccine is administered.

[0121] In another experiment, 1 to 5 doses of anti-IL-4R antibody were administered at different doses before vaccination with aP. Animals in each group will receive 1 mg / kg of mouse body weight. Animals in one group will also receive anti-IL-4R antibody at the same time as the aP vaccine. Animals in one group will receive priming A further booster dose of aP vaccine is administered 4 weeks after the first dose.

[0122] Serum was collected from naive and immunized mice 7 and 21 days after vaccination. Antigen-specific serum antibodies were analyzed by ELISA using plate-bound, heat-killed Bordetella pertussis or FHA (5 mg / mL). Bound antibodies were detected using biotin-conjugated anti-mouse IgG, IgG1, IgG2a, or IgG2c antibodies and peroxidase-conjugated streptavidin. Antibody levels were expressed as mean endpoint titers determined by extrapolation of the linear portion of the titration curve to 2 SD above the background value obtained with non-immunized mouse serum.

[0123] Prior to and / or concurrently with aP vaccination, low doses of anti-IL-4R antibodies were administered. Treated mice are expected to show a switch from serum IgG1 to serum IgG2a / c antibodies and a decrease in IgE concentrations. Furthermore, even a single dose of anti-IL-4R antibody administered prior to vaccination with the aP vaccine will result in a reduction in serum IgG1 levels and an increase in serum IgG2a / c antibodies. It is expected that low doses of anti-IL-4Rα treatment before and / or during vaccination will result in an increase in a / c levels and a decrease in IgE levels (i.e., a switch from Th2 to Th1 responses). Therefore, immunization with aP vaccines may be beneficial. It reduces the induced Th2 response and enhances the Th1 response.

[0124] Example 7: IL-4R Blockade as an Adjuvant for aP Vaccine in an Infant Baboon Model Cut off The efficacy of anti-IL-4R antibodies as adjuvants for acellular pertussis (aP) vaccines was investigated. The anti-IL-4Rα antibody used in this example has the amino acid sequence of SEQ ID NO: 14. and an LCVR having an amino acid sequence comprising SEQ ID NO: 15 (referred to herein as "mAb1").

[0125] The study design is summarized in Table 2.

[0126] [Table 2]

[0127] Baboons are immunized intramuscularly with human doses of aP or wP at 2, 4, and 6 months of age. For studies using aP, animals are vaccinated with Daptacel (Sanofi Pasteur) or Infanrix (GlaxoSmithKline). For studies using wP, animals are vaccinated with triple antigen (Serum Institute of India). Non-vaccinated animals are also age-matched. All animals receive fixed doses of placebo or mAb1 subcutaneously at 1, 2, 3, 4, 5, and 6 months of age, except for group 5, which receives fixed doses of mAb1 at 2, 4, and 6 months of age (Table 2). Whole blood is collected at 1, 2, 3, 4, 5, and 6 months of age for serum and PBMCs. Serum is analyzed for mAb1 levels and for IgG4-associated ... Pertussis-specific total IgG, IgG1, IgG4, and IgE levels are elevated. Animals are challenged with Bordetella pertussis at 6-8 months of age.

[0128] Animals treated with anti-IL-4R antibodies prior to vaccination with aP produced pertussis-specific Ig These animals are expected to show an increase in pertussis-specific IgG1 levels (Th1 specific) and a decrease in pertussis-specific IgG4 levels (Th2 specific). More importantly, animals treated with anti-IL-4R antibodies prior to vaccination with the aP vaccine are protected against disease upon Bordetella pertussis challenge, as evidenced by faster clearance of the bacterial infection from the lungs. will be done.

[0129] Example 8: Acellular pertussis vaccine in combination with anti-IL-4R antibodies in adolescents aged 10-15 years Clinical trials of Kuching The efficacy of anti-IL-4R antibodies as adjuvants was evaluated in adolescents aged 10-15 years. The efficacy of the acellular pertussis vaccine (TDaP, Adacel®, Sanofi Pasteur) in combination with dupilumab will be measured in clinical trials. One objective of the study is to study the efficacy of the acellular pertussis vaccine (TDaP, Adacel®, Sanofi Pasteur) in combination with dupilumab. Dupilumab is a fully human anti-IL-4R antibody containing a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NO:1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NO:3-8. It is an antibody.

[0130] Study treatment involves a 400 mg loading dose of dupilumab on day 1, followed by a 200 mg weekly dose; or a double placebo dose on day 1, followed by a weekly placebo dose. Study subjects receive subcutaneous injections of 200 mg of dupilumab or placebo on days 8, 15, 22, 29, 36, and 43. On day 29, all subjects receive a single dose of TDaP (Adacel®, sanofi) vaccine. Subjects are monitored for allergic reactions to the vaccine. Vaccine-specific serum Ig titers are checked 1, 4, 8, 16, and 24 weeks after vaccine injection.

[0131] The efficacy variables measured in this study include: (a) IgE titer; (b) FHA-specific total IgG titer; and (c) FHA-specific IgG1 and IgG4 titers.

[0132] The primary endpoint of the study is the proportion of dupilumab-treated subjects with a positive response to the vaccine on Day 43. A positive response is defined as one or more of the following, compared to placebo: (i) lower IgE titers in dupilumab-treated test subjects; (ii) higher vaccine-specific (e.g., anti-FHA) IgG4 titers in dupilumab-treated test subjects; and (iii) fewer adverse events (allergic reactions) in dupilumab-treated test subjects.

[0133] At the end of the study, subjects treated with dupilumab have one or more of the following: (a) lower IgE titers compared to placebo; (b) higher anti-FHA total IgG titers compared to placebo; (c) lower IgG4 and higher IgG1 titers compared to placebo. Greater than 50% of subjects in the study show a positive response to the vaccine.

[0134] Example 9: Acellular pertussis vaccine in combination with anti-IL-4R antibody in children under 10 years of age Clinical trial of booster dose of thiamin The efficacy of anti-IL-4R antibodies as adjuvants was evaluated in clinical trials in children under 10 years of age. One objective of the study is to test the efficacy of acellular pertussis vaccine (DTaP, Sanofi Pasteur) in combination with dupilumab. a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NO:1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NO:3 to SEQ ID NO:8.

[0135] Study treatment includes a 50 mg loading dose of dupilumab on day 1, followed by a 25 mg dose; or a double placebo dose on day 1, followed by a placebo dose. Study subjects receive subcutaneous injections of 25 mg of dupilumab (or placebo) every other week on days 15, 29, 43, 57, 71, 85, 99, and 113; followed by secondary dose injections on days 141, 155, 162, 169, 176, and 183. All subjects receive a vaccine dose (DTaP) on day 43, followed by booster doses on days 113 and 176.

[0136] Subjects will be monitored for allergic reactions to the vaccine. Vaccine-specific serum Ig titers will be checked 1, 4 and 8 weeks after each vaccine dose.

[0137] The efficacy variables measured in this study include: (a) IgE titer; (b) FHA-specific total IgG titer; and (c) FHA-specific IgG1 and IgG4 titers.

[0138] The primary endpoint of the study is the proportion of dupilumab-treated subjects who have a positive response to the vaccine on day 1. A positive response is defined as one or more of the following, compared to placebo: (i) a lower IgE titer in dupilumab-treated test subjects; (ii) a higher vaccine-specific (e.g., anti-FHA) IgG1 titer in dupilumab-treated test subjects; and (iii) a lower number of adverse events (allergic reactions) in dupilumab-treated test subjects.

[0139] At the end of the study, subjects treated with dupilumab have one or more of the following: (a) lower IgE titers compared to placebo; (b) higher anti-FHA total IgG titers compared to placebo; (c) lower IgG4 and higher IgG1 titers compared to placebo. More than 50% of subjects in the study show a positive response to the vaccine. More than 50% of subjects treated with dupilumab show higher IgG1 titers.

[0140] Example 10: Clinical Trial to Examine Vaccine Response in Adults with Atopic Dermatitis Treated with Dupilumab This was a 32-week, randomized, double-blind, placebo-controlled, parallel-group study evaluating the immune response to adsorbed tetanus toxoid Adacel® (tetanus, diphtheria, and acellular pertussis [TDaP]) and Menomune (meningococcal polysaccharide vaccine) vaccination in adults with moderate to severe AD treated with subcutaneously administered dupilumab. Eligible patients (194 patients) were randomized 1:1 to receive dupilumab or placebo for 16 weeks. Randomization was stratified by baseline disease severity (moderate vs. severe IGA). The treatment period was 16 weeks, followed by a 16-week follow-up period.

[0141] Test Purpose The primary objective of the study was to evaluate T cell-dependent vaccine responses in patients with moderate to severe atopic dermatitis (AD) inadequately controlled with topical medications who were treated with dupilumab 300 mg subcutaneously (SC) once weekly.

[0142] The secondary objectives of the study were (i) to evaluate the T cell-dependent vaccine response in patients with moderate to severe AD treated with dupilumab 300 mg SC once weekly; (ii) to evaluate the efficacy and safety of dupilumab in patients with moderate to severe AD; (iii) the safety of co-administered vaccine and SC dupilumab in patients with AD; and (iv) the efficacy of dupilumab in patients with moderate to severe AD.

[0143] The primary endpoint in the study was the proportion of patients with a positive response to tetanus toxoid (Adacel [TDaP] vaccine) at study week 16 (i.e., 4 weeks after immunization). A positive response was defined as a 4-fold or greater increase in anti-tetanus IgG titer from baseline 4 weeks after administration of Adacel for patients with a baseline titer ≥ 0.1 IU / mL, or a titer ≥ 0.2 IU / mL for patients with a baseline titer < 0.1 IU / mL.

[0144] Secondary endpoints were (i) the proportion of patients with a positive response at study week 16, with a positive response defined as a ≥2-fold increase in anti-tetanus IgG titer from pre-vaccination baseline for patients with a pre-vaccination tetanus antibody titer ≥0.1 IU / ml, or a titer ≥0.2 IU / ml for patients with a pre-vaccination titer <0.1 IU / ml; (ii) Menomune response: an SBA titer ≥8 for serogroup C (Immunological Basis for Immunization Series Module 15: Meningococcal Disease, World Health Organization 2010); (iii) the proportion of patients achieving investigator global assessment ([IGA](0-1)) at 16 weeks; (iv) the proportion of patients achieving IGA at 16 weeks (v) the proportion of patients achieving at least a 50% reduction in Eczema Area and Severity Index (EASI) score at week 16; (vi) the change from baseline in maximum pruritus numerical rating scale (NRS) at week 16; (vii) the change from baseline in BSA at week 16; (viii) the change from baseline in Global Symptom Score (GISS) erythema at week 1; (ix) the change from baseline in GISS erythema at week 16. (x) change from baseline in GISS infiltration / papulation at week 16; (xi) change from baseline in GISS lichenification at week 16; (xii) change from baseline to week 16 in Patient-Oriented Eczema Evaluation Score (POEM); (xiii) occurrence of serious treatment-emergent adverse events (TEAEs) during week 20; (xiv) occurrence of study drug discontinuation due to TEAEs during week 20; and (xv) occurrence of skin infections during week 20.

[0145] Test Design The study consisted of a screening period, a treatment period, and a follow-up period. Patients received weekly injections of dupilumab from day 1 through week 15. After providing appropriate training in self-injection, patients / caregivers self-injected dupilumab for several weeks, with no scheduled clinic visits (weeks 5, 6, 7, 9, 10, 11, 13, 14, and 15). Sites contacted patients by phone to schedule visits at weeks 5, 6, 7, 9, 10, 11, 13, 14, and 15. At week 12, patients received the Adacel (TDaP) and Menomune vaccines. Responses to vaccination (anti-tetanus IgG titers and serum bactericidal antibody (SBA) titers to meningococcal serogroups) were assessed 4 weeks later.

[0146] Patients who used or did not use relievers, mild to higher potency topical corticosteroids, and / or topical calcineurin inhibitors were potentially eligible for enrollment. Patients could be treated with topical AD therapy and / or low-dose systemic corticosteroids (prednisone or its equivalent ≤ 10 mg) at any time during the study and continue on study drug. A single course of high-dose systemic corticosteroids (any steroid dose prednisone or its equivalent > 10 mg) was used as rescue medication for up to 14 days after initiation and completed between Day 1 and Week 10 during the study, but study drug was not discontinued. Patients treated with high-dose systemic corticosteroids for AD were allowed to restart study drug for 5 half-lives after stopping systemic corticosteroids, as long as they did not experience a clinically significant adverse event (AE) related to the specific immunosuppressant and after consultation and consent from the medical monitor. After 10 to 16 weeks, high-dose systemic corticosteroids were prohibited.

[0147] For the dupilumab cohort, patients received a loading dose of 600 mg SC on day 1, followed by 300 mg qw from weeks 1 to 15.

[0148] For the placebo cohort, patients received a loading dose, SC, on day 1, followed by weekly placebo SC doses from weeks 1 through 15.

[0149] Adacel (TDaP) Vaccine: Patients were vaccinated with Adacel (TDaP) vaccine, IM, at 12 weeks.

[0150] Menomune vaccine: Patients were vaccinated with Menomune vaccine, SC, at 12 weeks.

[0151] Adacel (Tdap), manufactured by Sanofi Pasteur, was provided in prefilled syringes. Each 0.5 mL dose contained 5 Lf (agglutinating units) of tetanus toxoid (T), 2 Lf of diphtheria toxoid (d), and acellular pertussis antigens (2.5 μg of detoxified pertussis toxin, 5 μg of filamentous hemagglutinin [FHA], 3 μg of pertactin [PRN], and 5 μg of type 2 and 3 fimbriae [FIM]). Other components per 0.5 mL dose included 1.5 mg of aluminum phosphate (0.33 mg of aluminum) as an adjuvant, ≦5 μg of residual formaldehyde, <50 ng of residual glutaraldehyde, and 3.3 mg of phenoxyethanol (not as a preservative) (0.6% v / v). The antigens were the same as those in DAPTACELR, diphtheria and tetanus toxoids, and adsorbed acellular pertussis vaccine (DTaP), but the Adacel (Tdap) vaccine was formulated with reduced amounts of diphtheria and detoxified pertussis toxin. Menomune, manufactured by Sanofi Pasteur, was provided in single-dose vials for SC use. The single-dose diluent (0.6 mL) contained sterile, pyrogen-free, distilled water without preservatives. The multi-dose diluent (6 mL) contained sterile, pyrogen-free, distilled water and thimerosal, a mercury derivative, added as a preservative for the reconstituted vaccine.

[0152] Study population The target population included adults with moderate to severe AD whose disease was not adequately controlled with topical medications, including those who were not suitable candidates for treatment with effective topical therapies.

[0153] Inclusion Criteria: Patients had to meet the following criteria to be eligible for inclusion in the study: (1) Chronic AD (American Years with (according to the Academy of Dermatology Consensus Criteria, [Eichenfeld 2004]) (2) Male or female adults aged 18-64 years; (3) Eczema Area and Severity Index (EASI) score ≥ 16 at the screening and baseline visits; (4) Investigator Global Assessment (IGA) score ≥ 3 (IGA scale 0-4) at the screening and baseline visits; and (5) body surface area lesions of AD improvement ≥ 10% at the screening and baseline visits.

[0154] Note regarding the second criterion: An inadequate response was defined as failure to achieve or maintain remission or low disease activity (IGA 0 = eliminated to 2 = mild) despite treatment with a daily regimen of moderate- to higher-potency topical corticosteroids (with or without a topical calcineurin inhibitor, as needed) applied for at least 28 days or the maximum duration recommended by the product prescribing information (e.g., 14 days for ultra-potent topical corticosteroids), whichever is shorter. Patients with documented systemic treatment for AD in the past 6 months were also considered inadequate responders to topical treatment and were eligible for treatment with dupilumab after appropriate resolution. Serious side effects or safety risks outweighed the potential benefits of treatment and included treatment intolerance, hypersensitivity reactions, significant skin atrophy, and systemic effects, as assessed by the investigator or the patient's physician. Acceptable documentation included in contemporaneous charts described documented topical prescriptions and treatment outcomes or investigator documentation based on communication with the patient's primary care physician. If documentation was insufficient, potential patients were rescreened after such documentation was obtained (e.g., patients who demonstrated failure to complete a 28-day course of medium- to higher-potency topical corticosteroids [with or without topical calcineurin inhibitors]).

[0155] Patients were treated with emollients, topical corticosteroids + / - topical calcineurin inhibitors Patients could enroll in either or neither trials, but had to meet the following requirements: (i) patients treated with topical AD medications at baseline had to be on a stable dosing regimen for at least 14 days, or the maximum duration of treatment recommended by the prescribing information, whichever was shorter; and (ii) patients not treated with topical AD medications at baseline may not have used them within 7 days prior to the baseline visit.

[0156] Methods and Evaluation The efficacy of dupilumab in this population was assessed by measuring tetanus IgG titers and meningococcal serogroup SBA titers, quality of life questionnaires, and patient-reported outcomes. Response to the vaccine was assessed by measuring tetanus IgG titers and meningococcal serogroup SBA titers.

[0157] Analysis Variables The following demographic and baseline characteristic variables were summarized:

[0158] Demographic variables: age at screening (years), age group (<65, >=65), sex, ethnicity, race, baseline weight (kg), height (m), and BMI (kg / m2).

[0159] Baseline characteristics: (i) AD disease duration, (ii) immunoglobulin isotypes (total IgG, IgM, IgA, and IgE), anti-tetanus IgG titers, and SBA titers for group A, C, Y, and W-135 polysaccharide antigens, (iii) pruritus counts Atopic dermatitis (AD)-related parameters, including the Numerical Rating Scale (NRS), Investigator's Global Assessment (IGA) score, Eczema Area and Severity Index (EASI) score, Global Symptom Score (GISS), Atopic Dermatitis Body Surface Area (BSA) lesions, Patient Global Assessment of Disease Status, and Patient Oriented Eczema Evaluation Score (POEM). AD-related parameters are described in U.S. Publication No. 2014 / 0072583, which is incorporated herein by reference in its entirety.

[0160] Statistical Plan The full analysis set (FAS) included all randomized patients who received any study medication; it was based on treatment assignment (randomization). Efficacy endpoints were analyzed using the FAS. The safety analysis set (SAF) included all randomized patients who received any study medication; it was based on treatment received (treated). Treatment compliance / administration and all clinical safety variables were analyzed using the SAF. Responders to tetanus vaccination at week 16 of the study were investigated by comparing the proportion of positive responders between dupilumab and placebo using the Cochran-Mantel-Haenszel (CMH) test stratified by randomization stratum (disease severity). 90% CIs are presented with exploratory p-values. For continuous endpoints, a mixed-effects model with repeated measures (MMRM) was used. This model included factors for treatment (fixed effects), randomization stratum (disease severity), study visit, treatment by visit interaction, and relevant baseline values. Statistical inference was derived from the MMRM. Least squares means and 90% CIs were derived from the MMRM model and no p-values ​​were provided.

[0161] result Demographic and baseline characteristics are presented in Tables 3-6.

[0162] [Table 3]

[0163] [Table 4]

[0164] [Table 5]

[0165] [Table 6]

[0166] Positive response to tetanus toxoid at week 16 in the dupilumab treatment group The proportion of patients (83.3%) was similar to that in the placebo-treated treatment group (83.7%). The 90% CI for the difference between the treatment groups was (-9.41%, 8.69%).

[0167] Secondary measures of response included: the proportion of patients with a positive response to tetanus vaccination, defined as a 2-fold or greater increase in anti-tetanus IgG titer 4 weeks after vaccination (week 16); and the proportion of patients with a positive response to Menomune, defined as a serum bactericidal antibody (SBA) response to serogroup C of ≥8 4 weeks after vaccination (week 16).

[0168] A similar proportion of patients in the dupilumab-treated group (95.6%) achieved a 2-fold or greater increase in anti-tetanus IgG titers compared with placebo-treated patients (94.6%). Uniform responses to Menomune vaccine were also observed for both treatment groups; 86.7% of dupilumab-treated patients achieved an SBA >8 compared with 87.0% for placebo-treated patients. The 90% CI for the differences between treatment groups in tetanus toxoid (2-fold or greater increase) and Menomune responses were (-4.29%, 6.06%), respectively. 0.27%) and (-8.54%, 7.96%). However, dupilumab Patients treated with tetanus toxoid showed reduced toxicity (e.g., skin reactions) associated with tetanus toxoid compared to placebo.

[0169] The results of other secondary efficacy endpoints are presented in Table 7.

[0170] [Table 7]

[0171] Further analyses will include total IgE, and FHA-specific IgG1 and IgG4 titers in placebo- and dupilumab-treated patients. Patients treated with mab are expected to have lower IgE titers compared to placebo.

[0172] Patients on dupilumab had significantly lower total IgE compared to placebo (Table 8).

[0173] [Table 8]

[0174] IgE levels in response to TDaP vaccine components [pertussis toxin (PT), pertussis pertactin (PRN), and tetanus toxoid (TT)] were analyzed. In addition to vaccine-specific IgE, two allergens were included in the analysis (Fel d 1, a cat allergen, and Bet v 1, a birch allergen). Allergic antibody responses to allergens and TDaP antigens were assessed by measuring Fel d 1, Bet v 1, tetanus toxoid (TT), pertussis toxin (PT), and pertussis pertactin (PRN) IgE levels via a modified Luminex® antibody assay. Sera from weeks 12 (time of TDaP immunization), 16 (end of treatment period), and 32 (end of study) were treated with GullSORB™ and incubated with Fel d 1, Bet v 1, TT, PT, or PRN-coated microparticles. Bound specific IgE levels were assessed using R-Fib. Detected via anti-hIgE antibody conjugated with coerythrin (PE), TDaP TT-, P The mean fluorescence intensity (MFI) was expressed as T-, PRN-, or allergen Fel d 1- or Bet v 1-specific IgE. Values ​​3 SD above the mean of negative control sera were considered IgE-positive for the respective TDaP antigen or allergen.

[0175] IgE responses to Fel d 1 tended to be lower, and IgE responses to Bet v 1 were significantly lower in individuals treated with dupilumab, particularly at week 32 (end of study). 54 and 12.1% of individuals treated with dupilumab versus 65.2% and 30.4% of individuals treated with placebo were positive for Fel d 1-specific IgE (p=0.067) and Bet v 1-specific IgE (p<0.001), respectively, at week 32. The allergic status of the patients to these allergens was unknown.

[0176] Dupilumab- and placebo-treated patients had similar TDaP-specific IgE MFI, but placebo-treated patients showed a higher frequency of eliciting TDaP-specific IgE responses. Table 9 shows TDaP-specific IgE seropositivity in placebo- and dupilumab-treated patients at weeks 12 (time of TDaP immunization), 16 (end of treatment period), and 32 (end of study).

[0177] [Table 9]

[0178] As shown in Table 9, the majority of patients treated with dupilumab (62.16%) were seronegative for vaccine-specific IgE at the end of the study (week 32) compared to placebo (34.78%).

[0179] Overall, individuals treated with dupilumab had a significant reduction in total IgE (-54.7% from baseline) compared with placebo-treated individuals (-7.2%) by the end of the study (p=<0.0001). Patients treated with dupilumab were less likely to develop a TDaP-specific IgE response. By week 32 (end of study), 37.8% of dupilumab-treated patients versus 65.22% of placebo-treated patients had developed TDaP-specific IgE antibodies (the majority of patients were TDaP IgE-positive for all three vaccine antigens measured).

[0180] FHA-specific IgG1 and IgG4 titers were determined in placebo-treated and dupilumab-treated patients at weeks 4, 16, and 32. Patients receiving dupilumab showed a significant increase in FHA-specific IgG1 at weeks 4 and 16 after vaccination, but no treatment-specific response was observed. Due to their age, it was noted that patients may have received a full course of wP during their childhood. If true, this indicated a Th1 bias in wP-primed patients that was maintained into adulthood.

[0181] safety Treatment-emergent AEs (TEAEs, AEs that occurred during treatment and follow-up and worsened in severity compared with baseline) and potentially treatment-emergent clinically significant values ​​(PCSV) in laboratory variables, ECG, and vital signs were examined. There were three serious TEAEs in pilumab patients (3.1%): one stage IV mycosis fungoides, one squamous cell carcinoma, and one serum sickness-like reaction. There were no serious treatment-emergent adverse events in the placebo group. The incidence of treatment-emergent adverse events was lower in the dupilumab group compared with the placebo group (55.7% vs. 61.9%, respectively). Review of adverse events by MedDRA System Organ Class (SOC) did not reveal any suggestive patterns of adverse drug effects on specific organ systems. The most commonly reported SOCs were "infections and infestations" (32.0% for placebo vs. 35.1% for dupilumab), "general disorders and administration site conditions" (7.2% for placebo vs. 16.5% for dupilumab), "skin and subcutaneous tissue disorders" (16.5% for placebo vs. 7.2% for dupilumab), "respiratory, thoracic, and mediastinal disorders" (10.3% for placebo vs. 7.2% for dupilumab), and "gastrointestinal disorders" (5.2% for placebo vs. 11.3% for dupilumab). The most common TEAEs included upper respiratory tract infections (14.4% for placebo vs. 11.3% for dupilumab), atopic dermatitis (11.3% for placebo vs. 1.0% for dupilumab), and nasopharyngitis (5.2% for placebo vs. 4.1% for dupilumab). The dupilumab-treated group showed a lower incidence of injection site reactions, localized swelling or lymph node swelling associated with the vaccine injection compared to placebo.

[0182] conclusion Dupilumab did not suppress patient responses to the T cell-dependent vaccine (dTap) or the T cell-independent vaccine (Menomune). The response of patients treated with dupilumab 300 mg qw to the T cell-dependent vaccine (dTap) and the T cell-independent vaccine (Menomune) was comparable to that of patients treated with placebo. All secondary efficacy endpoints showed statistically significant favorable outcomes in the dupilumab group. Dupilumab 300 mg qw was safe and well tolerated. The safety profile of dupilumab was found to be consistent with that seen in previous studies.

[0183] Example 11: Duration of Th1 vs. Th2 responses to pertussis vaccine in human subjects

[0184] This example examines the duration of Th1 / Th2 responses to pertussis vaccine in human subjects primed with whole-cell (wP) or acellular pertussis (aP) vaccines during childhood. Individuals primed with wP or aP vaccines were divided into six groups. Individuals primed with wP or aP were boosted with wP, aP, or no vaccine (control). Antibody isotypes (total and antigen-specific IgG isotypes and IgE) were tested in the groups. Initial studies examined T cell responses in these individuals (Bancroft et al. 2016; 304-305: 35-43).

[0185] Individuals primed with wP are expected to exhibit antibody isotypes specific for Th1 responses (increases in antigen-specific serum IgG1 levels), regardless of whether they are boosted with aP or wP. Similarly, individuals primed with aP, regardless of aP / wP boosting, exhibit antibody isotypes specific for Th2 responses (increases in antigen-specific serum IgG4 levels). This indicates that responses triggered in response to initial vaccination with aP (Th2-specific responses) or wP (Th1-specific responses) persist throughout adulthood.

[0186] Based on the results, it is suggested that an IL-4R antagonist be administered at and / or before the priming dose. Individuals who have received the aP vaccine may be administered an anti-IL-4R antibody prior to and / or concurrently with the aP vaccine to imprint a Th1 response at the time of primary vaccination.

[0187] Example 12: Comparison of anti-IL-4R antibodies as adjuvants with other adjuvants

[0188] This example examines the effectiveness of an anti-IL-4R antibody as an adjuvant compared with other adjuvants. The anti-IL-4Rα antibody used in this example was an anti-mouse IL-4R antibody containing an HCVR having the amino acid sequence of SEQ ID NO: 11 and an LCVR having the amino acid sequence comprising SEQ ID NO: 12 ("anti-IL-4Rα").

[0189] Mice were immunized with ovalbumin as a model antigen in combination with different adjuvants, such as alum, AS04, AS03, MF59, and anti-IL-4Rα. Serum total and antigen-specific antibodies were analyzed. Administration of anti-IL-4Rα was predicted to boost ovalbumin immunity and induce a Th1 response compared with ovalbumin itself.

[0190] In another experiment, anti-IL-4Rα was administered in combination with ovalbumin and alum. Alum is known in the art to induce Th2 responses. Here, administration of anti-IL4Rα is expected to act as an immunological modulator / blocker specific to alum, causing a switch in Th1 responses.

[0191] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. 1. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist for use in a method of reducing vaccine-specific IgE induced by a vaccine against a bacterial or viral infection in a subject, the method comprising: administering the IL-4R antagonist to the subject; wherein the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3); the HCDR1 comprises the amino acid sequence of SEQ ID NO:3; the HCDR2 comprises the amino acid sequence of SEQ ID NO:4; the HCDR3 comprises the amino acid sequence of SEQ ID NO:5; the LCDR1 comprises the amino acid sequence of SEQ ID NO:6; the LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8, the IL-4R antagonist is administered simultaneously with or within 24 hours of administering the vaccine; The pharmaceutical composition.

2. The method includes administering the IL-4R antagonist to the subject within 24 hours of administering the vaccine. The pharmaceutical composition of claim 1.

3. The method includes administering the IL-4R antagonist simultaneously with administration of the vaccine. The pharmaceutical composition of claim 1.

4. The method comprises administering the vaccine in an initial dose followed by one or more subsequent (booster) doses. The pharmaceutical composition according to any one of claims 1 to 3.

5. The method further comprises administering a dose of the IL-4R antagonist to the patient within 24 hours of each dose of the vaccine. Administered within a short time period, The pharmaceutical composition according to claim 4.

6. The method includes administering a dose of the IL-4R antagonist simultaneously with each dose of the vaccine. The pharmaceutical composition according to claim 4.

7. The method includes administering the IL-4R antagonist at a dose of 1 to 10 mg / kg of the subject's body weight, or at a dose of 1 mg, 2 mg, 3 mg, 5 mg, or 6 mg / kg of the subject's body weight. The pharmaceutical composition according to any one of claims 1 to 6.

8. The method includes administering the IL-4R antagonist at a dose of 10 to 600 mg. The pharmaceutical composition according to any one of claims 1 to 6.

9. The method includes administering the IL-4R antagonist at a dose of 200 mg or 300 mg. The pharmaceutical composition of claim 8.

10. The method includes administering the IL-4R antagonist at a dose of 100 mg. The pharmaceutical composition of claim 8.

11. The subject is a patient with moderate to severe atopic dermatitis. The pharmaceutical composition according to any one of claims 1 to 10.

12. The anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2. The pharmaceutical composition according to any one of claims 1 to 11.

13. The IL-4R antagonist is dupilumab or a biological equivalent thereof. The pharmaceutical composition according to any one of claims 1 to 12.

14. The method includes administering the IL-4R antagonist once a week, once every two weeks, once every three weeks, or once every four weeks. The pharmaceutical composition according to any one of claims 1 to 13.

15. The method includes administering the IL-4R antagonist subcutaneously. The pharmaceutical composition according to any one of claims 1 to 14.

16. The vaccine comprises an acellular pertussis vaccine. The pharmaceutical composition according to any one of claims 1 to 15.

17. The vaccine is a DTaP vaccine or a Tdap vaccine.

17. The pharmaceutical composition of claim 16.

18. The IL-4R antagonist is contained in a syringe, a pen delivery device, or an autoinjector delivery device. The pharmaceutical composition according to any one of claims 1 to 17.

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