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CN-122005864-A - Adeno-associated viral vector pharmaceutical compositions and methods

CN122005864ACN 122005864 ACN122005864 ACN 122005864ACN-122005864-A

Abstract

Provided herein are pharmaceutical compositions comprising recombinant adeno-associated virus (AAV), a salt excipient or buffer, a sugar, and a surfactant. Also provided herein are methods for treating or preventing a disease in a subject in need thereof by administering to the subject a therapeutically effective amount of the pharmaceutical composition.

Inventors

  • T. MARSHALL
  • J .bi
  • K. Oberi
  • Y.ZHANG
  • R. Depas

Assignees

  • 再生生物股份有限公司

Dates

Publication Date
20260512
Application Date
20201006
Priority Date
20191007

Claims (20)

  1. 1. A pharmaceutical composition for use in treating Bei Duishi's disease, wherein the pharmaceutical composition comprises: (a) Recombinant adeno-associated virus (rAAV); (b) Potassium chloride; (c) Potassium dihydrogen phosphate; (d) Sodium chloride; (e) Anhydrous disodium hydrogen phosphate; (f) Sucrose, and (E) Poloxamer (poloxamer) 188.
  2. 2. The pharmaceutical composition of claim 1, wherein the recombinant AAV comprises components ：AAV1、AAV2、AAV2tYF、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV.rh20、AAV.rh39、AAV.Rh74、AAV.RHM4-1、AAV.hu37、AAV.Anc80、AAV.Anc80L65、rAAV.7m8、AAV.PHP.B、AAV.PHP.eB、AAV2.5、AAV2tYF、AAV3B、AAV.LK03、AAV.HSC1、AAV.HSC2、AAV.HSC3、AAV.HSC4、AAV.HSC5、AAV.HSC6、AAV.HSC7、AAV.HSC8、AAV.HSC9、AAV.HSC10、AAV.HSC11、AAV.HSC12、AAV.HSC13、AAV.HSC14、AAV.HSC15 and aav.hscs 16 of one or more adeno-associated viral serotypes selected from the group consisting of.
  3. 3. The pharmaceutical composition of claim 1, wherein the rAAV is AAV9 or AAV10.
  4. 4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises one or more amino acids.
  5. 5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises an ionic strength of about 60 mM to about 115 mM.
  6. 6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises: (a) Potassium chloride at a concentration of about 0.2 g/L; (b) Potassium dihydrogen phosphate at a concentration of about 0.2 g/L; (c) Sodium chloride at a concentration of about 3.50 g/L to about 8.01 g/L, and (D) Anhydrous disodium hydrogen phosphate at a concentration of about 1.15 g/L.
  7. 7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises: (a) Potassium chloride at a concentration of about 0.2 g/L; (b) Potassium dihydrogen phosphate at a concentration of about 0.2 g/L; (c) Sodium chloride at a concentration of about 5.84 g/L, and (D) Anhydrous disodium hydrogen phosphate at a concentration of about 1.15 g/L.
  8. 8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises sucrose at a concentration of about 3% (w/v, 30 g/L) to about 18% (w/v, 180 g/L).
  9. 9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises sucrose at a concentration of about 4% (w/v, 40 g/L).
  10. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises poloxamer 188, and wherein the poloxamer 188 is at a concentration of about 0.0005% (w/v, 0.005 g/L) to about 0.05% (w/v, 0.5 g/L).
  11. 11. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises poloxamer 188, and wherein the poloxamer 188 is at a concentration of about 0.001% (w/v, 0.01 g/L).
  12. 12. The pharmaceutical composition of claim 1, wherein the rAAV comprises an AAV capsid and a vector genome packaged therein, and wherein the vector genome comprises: (a) AAV 5' Inverted Terminal Repeats (ITRs); (b) A promoter; (c) Transgenesis, and (d)AAV 3’ ITR。
  13. 13. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a Vector Genome Concentration (VGC) at a concentration of about 3.0 x 10 9 GC/mL to about 3 x 10 13 GC/mL.
  14. 14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a Vector Genome Concentration (VGC) at a concentration of about 1.0 x 10 11 GC/mL.
  15. 15. The pharmaceutical composition of claim 1, wherein the rAAV comprises a transgene associated with the treatment of Bei Duishi's disease.
  16. 16. The pharmaceutical composition of claim 1, wherein the rAAV comprises a transgene, wherein the transgene is CLN2.
  17. 17. The pharmaceutical composition of claim 1, wherein the rAAV comprises a transgene, wherein the transgene encodes a tripeptidyl peptidase 1 (TPP 1) protein.
  18. 18. The pharmaceutical composition of claim 1, wherein the AAV 5 'ITRs and/or the AAV 3' ITRs are from AAV2.
  19. 19. The pharmaceutical composition of claim 1, wherein the promoter is a Chicken Beta Actin (CBA) promoter.
  20. 20. The pharmaceutical composition of claim 1, wherein the promoter is a hybrid promoter comprising a CBA promoter sequence and a cytomegalovirus enhancer element.

Description

Adeno-associated viral vector pharmaceutical compositions and methods The application is a divisional application, the application date of the original application is 10/6/2020, the application number is 202080079668.3 (International application number PCT/US 2020/054400), and the name is 'adeno-associated virus vector pharmaceutical composition and method'. Cross reference to related applications The present application claims the benefit of U.S. provisional application No. 62/911,968 filed on 7 of 10.2019, the contents of which are incorporated herein by reference in their entirety. Reference to an electronically submitted sequence Listing The present application incorporates by reference a sequence_listing_12656-124-228.Txt, entitled "sequence_listing_12656-124-228.Txt" created at 9/28/2020 and having a size of 97,652 bytes, filed with the present application, as a text file. Background Adeno-associated viruses (AAV), which are members of the parvoviridae family designated as virus-dependent, are small non-enveloped icosahedral viruses with single-stranded linear DNA genomes of about 4.7 kilobases (kb) to 6 kb. The non-pathogenic, broad host and cell type tropism range of infectivity, including dividing cells and non-dividing cells, and the nature of the ability to establish long-term transgene expression make AAV an attractive tool for gene therapy (e.g., gon ç alves, 2005, virology Journal, 2: 43). AAV products are typically stored in buffers composed of various excipients to stabilize the product during manufacture, transport, storage, and management. However, AAV biotherapeutic drugs are distributed at-80 ℃ to prevent degradation and the negative effects of potential material thawing, even if delivered to certain areas may not provide adequate refrigeration at these temperatures. Maintaining the freezer temperature at +.60 ℃ is a challenge and from a logistical standpoint it is desirable to provide a formulation that is robust to higher freezing temperatures (e.g., up to-20 ℃) and stable to multiple freeze-thaw excursions. Not all clinical sites have-80 ℃ freezers and this requirement can negatively impact the ability to distribute the product to a wide range of clinical sites. Thus, a formulation that is stable for a short duration (up to 12 months) under refrigerated conditions is desired to allow the clinical site to thaw and store the product in a freezer until the patient is scheduled for administration. Maintaining various cushioning characteristics within target specification ranges is critical to ensure product stability, but storage at-80 ℃ can affect supply chain and distribution. Crystallization of water during slow freezing can lead to concentration of excipients, which can affect the stability of the biologic. Phase separation or pH changes may also occur, which may affect the stability of the biological agent. For commercialization of any pharmaceutical product, it would be advantageous to identify formulations that provide stability for extended periods of time. It would be further advantageous to identify formulations that are stable under frozen storage at-20 ℃ to account for frozen temperature drift, variability, or temporary storage in a-20 ℃ freezer (up to 18 months), refrigerated conditions to allow short term storage in the clinic (up to 12 months at 2-8 ℃) prior to administration, at room temperature to allow manufacturing and labeling, or at multiple free defrost cycles to allow thawing of drug substances and drug products for filling and labeling operations. Disclosure of Invention The present disclosure provides a pharmaceutical composition comprising a recombinant adeno-associated virus (AAV), a buffer, an ionic salt, sucrose, and a surfactant such as poloxamer 188. Sucrose is provided at a concentration that prevents crystallization of the composition and maintains the pH between 6 and 9 during freezing and liquid phase. In some embodiments, the recombinant AAV comprises components from one or more adeno-associated viral serotypes selected from the group consisting of AAV1, AAV2tYF, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 and AAVrh10、AAV.rh20、AAV.rh39、AAV.Rh74、AAV.RHM4-1、AAV.hu37、AAV.Anc80、AAV.Anc80L65、rAAV.7m8、AAV.PHP.B、AAV.PHP.eB、AAV2.5、AAV2tYF、AAV3B、AAV.LK03、AAV.HSC1、AAV.HSC2、AAV.HSC3、AAV.HSC4、AAV.HSC5、AAV.HSC6、AAV.HSC7、AAV.HSC8、AAV.HSC9、AAV.HSC10、AAV.HSC11、AAV.HSC12、AAV.HSC13、AAV.HSC14、AAV.HSC15, or aav.hsc16. In some embodiments, the rAAV comprises capsid proteins of AAV8 or AAV9 serotypes. In some embodiments, the pharmaceutical composition further comprises an amino acid. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a recombinant adeno-associated virus (AAV), an ionic salt excipient or buffer, sucrose, and poloxamer 188. In some embodiments, the ionic salt excipient or buffer may be one or more components from the group consisting of potassium dihydrogen phosphate, potassium phosphate, sodium chloride, d