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EP-3937966-B1 - COMPOSITIONS AND METHODS FOR PROTECTING TYPE 2 ALVEOLAR EPITHELIAL CELLS (AEC2)

EP3937966B1EP 3937966 B1EP3937966 B1EP 3937966B1EP-3937966-B1

Inventors

  • WASNICK, Roxana
  • GUENTHER, ANDREAS

Dates

Publication Date
20260506
Application Date
20200311

Claims (14)

  1. A pharmaceutical composition comprising a recombinant peptide consisting of the amino acid sequence FTTFTVT (SEQ ID NO: 2) or a recombinant peptide or polypeptide comprising an amino acid sequence selected from any one of SEQ ID NOs: 3-10, for use in the treatment of infant respiratory distress syndrome or acute respiratory distress syndrome in a patient; wherein the administration of the pharmaceutical composition is for use in increasing the expression level of surfactant protein-C (Sp-C) protein in the lung epithelium of the patient.
  2. The pharmaceutical composition for use of claim 1, wherein the patient has acute respiratory distress syndrome.
  3. The pharmaceutical composition for use of claim 1, wherein the patient has infant respiratory distress syndrome.
  4. The pharmaceutical composition for use of any one of claims 1-3, wherein the method further comprises administering at least one additional therapeutic, wherein optionally the at least one additional therapeutic is an NSAID, steroid, DMARD, immunosuppressive, biologic response modulators, or bronchodilator.
  5. The pharmaceutical composition for use of any one of claims 1-4, wherein the recombinant peptide consists of the amino acid sequence of FTTFTVT (SEQ ID NO: 2).
  6. The pharmaceutical composition for use of any one of claims 1-4, wherein the recombinant peptide or polypeptide comprises the amino acid sequence of ASFTTFTVT (SEQ ID NO: 3).
  7. The pharmaceutical composition for use of any one of claims 1-4 and 6, wherein the recombinant peptide or polypeptide comprises at least one non-standard amino acid, wherein optionally, the non-standard amino acid is ornithine.
  8. The pharmaceutical composition for use of any one of claims 1-4 and 6-7, wherein the recombinant peptide or polypeptide comprises a N-terminal and/or C-terminal modification, wherein optionally, the N-terminal modification is acylation and/or the C-terminal modification is amidation.
  9. The pharmaceutical composition for use of claim 6, wherein the recombinant peptide or polypeptide comprises the amino acid sequence of KASFTTFTVTKGS (SEQ ID NO: 4), KASFTTFTVTKGS-NH2 (SEQ ID NO: 5), aaEGKASFTTFTVTKGSaa (SEQ ID NO: 6), or aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 7).
  10. The pharmaceutical composition for use of claim 7, wherein the recombinant peptide or polypeptide comprises the amino acid sequence of OASFTTFTVTOS (SEQ ID NO: 9) or OASFTTFTVTOS-NH2 (SEQ ID NO: 10).
  11. The pharmaceutical composition for use of claim 6, wherein the recombinant peptide comprises the amino acid sequence of Ac-aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 8).
  12. The pharmaceutical composition for use of any one of claims 1-11, wherein the recombinant peptide or polypeptide maintains the biological activity of caveolin-1 (Cav-1).
  13. The pharmaceutical composition for use of any one of claims 1-12, wherein the recombinant peptide or polypeptide: i) comprises L-amino acids or at least one D-amino acid; ii) is capped at N-terminus and/or C-terminus; iii) is conjugated with a heterologous polypeptide segment or polymer; optionally polyethylene glycol; iv) is linked at the N- or C-terminus to a heterologous domain; optionally an XTEN polypeptide, IgG Fc domain, albumin, or albumin binding peptide; v) is linked to a cell-binding domain or cell penetrating peptide; or vi) is chemically modified.
  14. The pharmaceutical composition for use of any one of claims 1-13, wherein the pharmaceutical composition is formulated for injection or lung instillation.

Description

BACKGROUND 1. Field The present invention relates generally to the fields of molecular biology and medicine. More particularly, it concerns compositions for use in treating infant respiratory distress syndrome or acute respiratory distress syndrome in a patient. 2. Description of Related Art Alveolar epithelial type 2 cells (AEC2) are the primary progenitor cell of the alveolar epithelium (Ten Have-Opbroek (1979) Dev. Biol. 69:408-423). In the embryo, AEC2 arise from multipotent stem cells which line the primitive respiratory tract. These primitive, proliferative embryonic epithelial precursors co-express several markers, including SP-A, SP-C, CC.10 and cGRP, which are subsequently expressed in separate, differentiated lineages in the mature fetus and in the adult, including AEC2, Clara cells, and pulmonary neuroendocrine cells (Wuenschell et al. (1996) J Histochem. Cytochem. 44:113-123). At late gestation, the AEC lineage becomes restricted, such that only AEC type 1 and type 2 cells are produced (Mason et al. (1997) Am. J Respir. Cell Mol. Biol. 16:355-363). Type 2 cells manufacture surfactant and can differentiate, as required, into AEC1 (Ten Have-Opbroek, et al. (1991) Anat. Rec. 229:339-354). AEC1 are terminally differentiated, incapable of dividing, and perform the necessary lung function of gas exchange. However, the ability to divide must be retained by a subpopulation within the lung alveolar epithelium throughout the life span of any animal, in order to replace damaged cells (Adamson and Bowden (1974) Lab Invest. 30:35-42; Evans, et al. (1975) Exp. Mol. Pathol. 22:142-150). Due to the important role that AEC2 cells play in maintaining lung health, compositions and methods for protecting AEC2 cells of apoptosis-inducing insults are greatly needed. M.R. Nagaraja et al. reports that p53 expression in lung fibroblasts is linked to mitigation of fibrotic lung remodeling (Am J Pathol. 2018; 188(10):2207-2222)). SUMMARY The invention is set out in the appended set of claims. In one embodiment, provided herein is a pharmaceutical composition comprising a recombinant peptide consisting of the amino acid sequence FTTFTVT (SEQ ID NO: 2) or a recombinant peptide or polypeptide comprising an amino acid sequence selected from any one of SEQ ID NOs: 3-10, for use in the treatment of infant respiratory distress syndrome or acute respiratory distress syndrome in a patient; and wherein the administration of the pharmaceutical composition is for use in increasing the expression level of surfactant protein-C (Sp-C) protein in the lung epithelium of the patient. In some aspects, the patient has infant respiratory distress syndrome. In some aspects, the patient has acute respiratory distress syndrome (ARDS). In some aspects, the patient is a human. In certain aspects, the patient is an infant. In some aspects, administering comprises nebulizing a solution comprising the peptide. In some aspects, the methods further comprise administering at least one additional therapeutic to the patient. In certain aspects, the at least one additional therapeutic is an NSAID, steroid, DMARD, immunosuppressive, biologic response modulators, or bronchodilator. In some aspects, the recombinant peptide consists of the amino acid sequence FTTFTVT (SEQ ID NO: 2). In some aspects, the recombinant peptide or polypeptide comprises the amino acid sequence ASFTTFTVT (SEQ ID NO: 3), and the peptide or polypeptide comprises at least one N- or C-terminal addition lacking identity to SEQ ID NO: 2. In some aspects, the recombinant peptide or polypeptide comprises at least one amino acid added to the N-terminus. In some aspects, the recombinant peptide or polypeptide comprises at least one amino acid added to the C-terminus. In some aspects, the recombinant peptide or polypeptide comprises at least one amino acid added to the N-terminus and the C-terminus. In some aspects, the recombinant peptide or polypeptide comprises at least one non-standard amino acid. In some aspects, the recombinant peptide or polypeptide comprises 2 non-standard amino acids. In certain aspects, the non-standard amino acid is ornithine. In some aspects, the recombinant peptide or polypeptide comprises a N-terminal modification. In some aspects, the recombinant peptide or polypeptide comprises a C-terminal modification. In some aspects, the recombinant peptide or polypeptide comprises a N- and C-terminal modification. In certain aspects, the N-terminal modification is acylation. In certain aspects, the C-terminal modification is amidation. In some aspects, the recombinant peptide or polypeptide comprises the amino acid sequence KASFTTFTVTKGS (SEQ ID NO: 4). In some aspects, the recombinant peptide or polypeptide comprises the amino acid sequence aaEGKASFTTFTVTKGSaa (SEQ ID NO: 6). In some aspects, the recombinant peptide or polypeptide comprises the amino acid sequence OASFTTFTVTOS (SEQ ID NO: 9). In some aspects, the recombinant peptide or polypeptide comprises the amino acid