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EP-4734956-A1 - MUCOADHESIVE FORMULATION

EP4734956A1EP 4734956 A1EP4734956 A1EP 4734956A1EP-4734956-A1

Abstract

The invention relates to dry powder formulations for mucosal administration comprising antibodies, bispecific antibodies or antigen-binding fragments that have broad binding activity against respiratory viruses, for example, influenza, respiratory syncytial virus and coronaviruses. The disclosure also relates to their methods of manufacture and the kits used for their administration to patients.

Inventors

  • MANFORD, Fergus
  • HSIEH, YI-HAN
  • MANNESSE, MAURICE

Assignees

  • Leyden Laboratories B.V.

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. 1. A dry powder composition comprising an antibody, a bispecific antibody or an antigen-binding fragment thereof, and at least one mucoadhesive compound, wherein the concentration of the antibody, bispecific antibody or antigen-binding fragment thereof ranges from 0.001 to 75 % (w/w) and the concentration of the mucoadhesive compound ranges from 0.1 to 10 % (w/w).
  2. 2. A composition according to Claim 1, wherein the concentration of said mucoadhesive compound ranges from 0.5 to 5 % (w/w).
  3. 3. A composition according to any one of Claims 1 or 2, wherein the average molecular weight of said mucoadhesive compound is at least 100 kDa.
  4. 4. A composition according to any one of Claims 1 to 3, wherein said mucoadhesive compound comprises at least one selected from the group consisting of cellulose derivatives, amylose, gellan gum, guar gum, karaya gum, xanthan gum, carrageenan, alginate, pectin, dextran, chitosan, agarose, hyaluronic acid, gelatin, pectin, tragacanth, poly (vinyl pyrrolidone) such as Kollidon VA 64, poly(dimethyl siloxane), poly acrylic acid-based polymers such as poly acrylates, plyethylene glycol, sodium alginate, polycarbophil such as Noveon AA-1, polylysene, dimethylaminoethyl dextran, poly vinyl alcohol, hydroxy ethyl starch, Carbopol 97 IP NF, Carbopol 974P NF, Carbopol 71G NF, and/or hydroxyl ethyl cellulose (HEC).
  5. 5. A composition according to Claims 1 to 4, wherein the mucoadhesive compound comprises at least one selected from the group consisting of Sodium carboxyl methyl cellulose (SCMC), methylcellulose, carboxylmethylcellulose (CMC), hydroxylpropyl cellulose, hydroxylpropyl methylcellulose (HPMC) and ethyl cellulose.
  6. 6. A composition according to any one of Claims 1 to 5, wherein the mucoadhesive compound comprises hydroxylpropyl methylcellulose (HPMC).
  7. 7. A composition according to any one of Claims 1 to 6, wherein the mucoadhesive compound comprises HPMC and wherein the HPMC comprises at least one of HPMC substitution type 2910, HPMC substitution type 1828, HPMC substitution type 2208 and HPMC substitution type 2906.
  8. 8. A composition according to any one of Claims 1 to 7, wherein the mucoadhesive compound comprises HPMC and wherein the HPMC comprises homogenously substituted HPMC cellulose, alternatively wherein the HPMC comprises heterogeneously substituted cellulose.
  9. 9. A composition according to any one of Claims 1 to 8, further comprising a preservative.
  10. 10. A composition according to Claim 9, wherein the preservative is selected from the group consisting of sodium acetate, benzalkonium chloride, potassium sorbate, calcium sorbate, methyl paraben, ethyl paraben, propyl paraben, phenylcarbinol, chlorolbutanol, chlorolcresol, Ethylenediaminetetraacetic acid (EDTA).
  11. 11. A composition according to any one of Claims 1 to 10, wherein the antibody, bispecific antibody or antigen-binding fragment thereof comprises CR9114.
  12. 12. A composition according to any one of Claims 1 to 11, wherein the composition is a controlled released composition.
  13. 13. A composition according to Claims 1 to 12, having a viscosity ranging from 2 to 120 (N s/m 2 ) as determined by a sheer stress method.
  14. 14. A composition according to Claims 1 to 13, wherein the viscosity of the composition ranges from 25 to 50 (N s/m 2 ), as determined by a sheer stress method.
  15. 15. An inhaler comprising the composition according to Claims 1 to 14.

Description

MUCOADHESIVE FORMULATION FIELD OF THE INVENTION The invention relates to formulations for mucosal administration comprising antibodies, bispecific antibodies or antigen-binding fragments that have broad binding activity against respiratory viruses, for example, influenza, respiratory syncytial virus and coronaviruses. The disclosure also relates to their methods of manufacture and the kits used for their administration to patients. BACKGROUND OF THE INVENTION Respiratory Viruses Influenza virus Seasonal influenza virus epidemics cause 3 to 5 million severe cases of influenza worldwide and 650,000 deaths each year. In 2018, it was estimated that the average annual total economic burden of influenza to the healthcare system and society in the United States alone was $11.2 billion. Thus, the ongoing healthcare burden is inadequately addressed with current therapies, z.e., vaccines and antivirals. The inadequacy of these therapies has been largely due to current vaccines only being effective against a specific and very narrow spectrum of viral strains. The influenza virus also poses pandemic threats (e.g., influenza virus H5). Respiratory syncytial virus While Respiratory syncytial virus (RSV) very rarely causes severe disease in healthy adults, it can cause morbidity and mortality in the elderly and in those with underlying immune compromise or cardiopulmonary disease. Older adults have a similar presentation to younger adults when infected with RSV but tend to have greater symptom severity with increased risk of lower respiratory tract involvement. In particular, the elderly are more likely to experience pneumonia, respiratory distress, and death. Globally, RSV affects an estimated 64 million people and causes 160,000 deaths each year. SARS-CoV-2 virus Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. Since the start of the CO VID-19 pandemic, there have been an estimated 767 million cases of SARS-CoV-2 virus infection and an estimated 6.9 million deaths. The continued spread of the virus is largely driven by the emergence of viral variants, which can evade the current vaccines through mutations in the spike protein. An example of an antibody with broad binding activity against influenza is the human monoclonal antibody (mAb) CR9114 which binds to the highly conserved stem region of hemagglutinin (HA), a receptor-binding glycoprotein relevant to viral entry. CR9114 can prevent fusion of the viral envelope with the endocytic vesicular membrane, and therefore protects individuals from influenza A virus subtypes Al or A2. CR9114 may deliver in vivo protection against Influenza virus B by preventing egress of newly formed virions from infected cells. Moreover, even though CR9114 does not bind to another surface protein Neuraminidase (NA), CR9114 is capable of inhibiting NA catalytic activity which is necessary for efficient viral egress through steric hindrance. Hence, CR9114 is eminently suited for use in a drug formulation for prophylactically and/or therapeutically treating influenza infections. The most common reason for introducing an antibody into the nasal cavity is to provide a convenient and accessible route for rapidly and efficiently managing the localized symptoms associated with infection. Small molecules have typically been applied to the nasal mucosa and these include antihistamines, corticosteroids, sodium cromoglicate, sympathomimetics and antiseptics/antibiotics. These molecules are administered either in liquid form (from a spray or as drops) or as creams/ointments. The nasal cavity has been used as a portal for the delivery of vaccines, particularly for vaccines against influenza infections. The presentation of an antigen to the nasal-associated lymphoid tissue can promote both cellular and humoral responses. The nasal vestibule is the first and narrowest part of the nasal cavity, with a cross-sectional area of approximately 30 mm2 on each side. The lining of the vestibule changes from skin at the entrance to a stratified squamous epithelium which extends over the anterior third of the entire nasal cavity. The nasal vestibule contains vibrissae which filter out inhaled particles with an aerodynamic particle size greater than approximately 10 pm. Progression through the nasal cavity leads to the turbinate region. The turbinates are convoluted projections from the nasal septum which are lined with a pseudostratified columnar epithelium (80% to 90% of the total surface area of the nasal epithelium in humans) composed of mucus-secreting goblet cells, ciliated and non-ciliated cells and basal cells. The apical surfaces of the ciliated and non-ciliated cells are covered with nonmotile microvilli, which serve to increase the surface area of the epithelial cells. There are also approximately 100 motile cilia on each ciliated cell which are responsible for mucus transport. Serous and seromucous glands also contribute to nasal secretions. As air moves through th