Treatment and/or prevention of sepsis
Inventors
Connaris, Helen • Taylor, Garry • Yesilkaya, Hasan • Andrew, Peter
Assignees
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Publication Number
US-10953078-B2
Publication Date
2021-03-23
Expiration Date
Abstract
The disclosure provides molecules with an affinity for (or an ability to bind to), sialic acid, for use in compositions, medicaments and methods for the treatment of sepsis, its symptoms and sepsis associated pathologies and immune responses.
Core Innovation
The disclosure describes sialic-acid binding molecules for treating and/or preventing sepsis and/or one or more symptoms thereof. The molecules comprise two or more family 40 carbohydrate binding molecules, and the document focuses on multivalent family 40 carbohydrate binding module (mCBM40) constructs.
A sialic-acid binding molecule includes family 40 carbohydrate binding molecules derived from sialidases, including Vibrio cholerae NanH and Streptococcus pneumoniae NanA. The disclosed constructs include multivalent formats such as Vc4CBM and oligomeric constructs such as Vc2CBMTD and Sp2CBMTD, including configurations involving a pseudaminidase trimerisation domain and NanH/NanA CBM units.
The mechanism described is dampening pro-inflammatory cytokine and pro-coagulation cascades and preventing pathogen exploitation of host sialic-acid receptors. The document reports example data in vivo in mouse models of pneumococcal challenge, including improved survival after challenge and reduced bacteraemia following intravenous and intranasal administration.
Claims Coverage
The independent claim covers a method of treating and/or preventing sepsis and/or one or more symptoms thereof by administering a sialic acid binding molecule comprising two or more family 40 carbohydrate binding molecules. The claim set includes 6 inventive features, with dependent features specifying NanH/NanA-derived domains, sequence identity options, defined multivalent architectures, and administration/formulation routes.
Treating or preventing sepsis with multivalent family 40 carbohydrate binding modules
A method of treating and/or preventing sepsis and/or one or more symptoms thereof by administering a sialic acid binding molecule to a subject with sepsis, an infection which could lead to sepsis, or a subject diagnosed as suffering from one or more sepsis associated pathologies, wherein the sialic acid binding molecule comprises two or more family 40 carbohydrate binding molecules.
Using sialic-acid binding domains from Vibrio cholerae NanH and/or Streptococcus pneumoniae NanA
The method wherein the sialic acid binding molecule comprises the sialic acid binding domain of Vibrio cholerae NanH sialidase and/or the sialic acid binding domain of Streptococcus pneumoniae NanA sialidase.
Vibrio cholerae NanH sequence identity options
The method wherein the Vibrio cholerae NanH sialidase includes the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
Defined multivalent and oligomeric architectures using Vc4CBM and/or Vc2CBMTD
The method characterized by using a sialic acid binding molecule formed by either four Vibrio cholerae NanH sialidase CBM units linked/bound/conjugated together (Vc4CBM) and/or two Vibrio cholerae NanH sialidase CBM units fused/bound/conjugated to a Pseudomonas aeruginosa pseudaminidase trimerisation domain (Vc2CBMTD).
Formulating for oral, mucosal, or parenteral administration
The method includes formulating the sialic acid binding molecule for oral, mucosal, or parenteral administration.
Formulating for intranasal administration
The method includes formulating the sialic acid binding molecule for intranasal administration.
Overall, the claim set centers on sepsis treatment/prevention via administration of a sialic acid binding molecule comprising two or more family 40 carbohydrate binding molecules, with dependent features specifying NanH/NanA-derived family 40 carbohydrate binding domains and sequence identity options, defined multivalent/oligomeric architectures, and selected administration/formulation routes including oral/mucosal/parenteral and intranasal.
Stated Advantages
Avoiding induction/acceleration of microbial pro-inflammatory component release compared with antibiotics/AMPs.
Lower toxicity/resistance risk.
Documented Applications
Treating or preventing sepsis and/or sepsis-associated symptoms/pathologies, including in contexts of an infection which could lead to sepsis.
Use in mouse survival after pneumococcus-infected challenge, including reported improved survival and reduced bacteraemia following intravenous and intranasal dosing.
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