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Publication Number
US-11466059-B2
Publication Date
2022-10-11
Expiration Date
Abstract
The present disclosure a cohort of sialic acid binding molecules which comprise one or more modified carbohydrate binding modules (CBMs). The modified CBMs reduce the risk of adverse events related to the host immune response and/or the production of anti-drug antibodies (ADAs). The modified CBMs can be used in therapy or as medicaments and find specific application as molecules for the modulation of an immune response and/or cell growth. The modified CBMs may also be used as adjuvants, for example mucosal adjuvants and in the treatment and/or prevention of cancer, sepsis and/or diseases caused or contributed to by a pathogen that binds cell surface sialic acid-containing receptors.
Core Innovation
The invention relates to sialic acid binding molecules constructed from modified carbohydrate binding modules (CBMs). The molecules include modified Family 40 (CBM40) domains for sialic acid binding, with the modification focus on reducing immunogenicity or antigenicity while maintaining or improving sialic acid binding and thermostability.
The described constructs may include an optionally modified oligomerization or trimerization domain in addition to the modified CBM40 domain. Immunogenic peptide clusters are identified using ProPred, ProImmune, and T-cell assays, and regions and modifications are selected to reduce anti-drug antibody and immune complex risks associated with anti-CBM antibodies.
Example molecules and multivalent constructs include HEX6 and HEX17 with an A162P mutation, and references to Sp2CBMTD/SpOrig and SpCBM from Streptococcus pneumoniae NanA sialidase CBM40 and PaTD from Pseudomonas aeruginosa pseudaminidase trimerization domain. Reported functional outcomes include reduced IL-8 and inflammatory mediator stimulation for HEX17 versus WT/HEX6, and immunological outcomes including reduced and/or altered anti-CBM antibody responses after repeat intranasal dosing.
The approach is evaluated in a lethal PR8 influenza model, with reported improved survival and lower clinical scores for HEX17 compared with reference constructs. Antibody measurements are described as showing reduced IgA/IgM after repeat intranasal dosing, and the invention describes de-immunized or reduced-immunogenicity sialic acid binding molecules built from modified CBM40 domains and optionally modified oligomerization or trimerization domains.
Claims Coverage
The independent claim covers a sialic acid binding molecule defined by a specific amino-acid sequence, SEQ ID NO: 28. Dependent claims refine the molecule into pharmaceutical compositions and narrow intended administration routes, including intranasal administration and inhalation, and include a related formulation preparation concept.
A sialic acid binding molecule comprising a specified amino-acid sequence
A sialic acid binding molecule comprising SEQ ID NO: 28.
A pharmaceutical composition including the sialic acid binding molecule with formulation aids
A pharmaceutical composition that includes the sialic acid binding molecule formulated with one or more formulation aids such as excipients, carriers, adjuvants, and/or buffers.
A pharmaceutical composition for oral, mucosal, or parenteral administration
A pharmaceutical composition formulated for oral administration, mucosal administration, or parenteral administration.
A pharmaceutical composition for intranasal administration or inhalation
A pharmaceutical composition formulated for intranasal administration or inhalation.
Preparing a pharmaceutical composition by formulating with excipients, carriers, adjuvants, and/or buffers
Preparing the pharmaceutical composition by formulating the sialic acid binding molecule together with excipients, carriers, adjuvants, and/or buffers.
Overall claim coverage centers on a specific sialic acid binding molecule sequence, SEQ ID NO: 28, and its incorporation into pharmaceutical compositions with formulation aids. The dependent claims then narrow administration routes to oral, mucosal, parenteral, and specifically intranasal administration or inhalation, and include a concept for preparing the formulated composition.
Stated Advantages
Reduced IL-8 and inflammatory mediator stimulation for HEX17 versus WT/HEX6.
Improved survival and lower clinical scores in a lethal PR8 influenza model for HEX17.
Reduced and/or altered anti-CBM antibody responses after repeat intranasal dosing.
Reduced IgA/IgM after repeat intranasal dosing.
Documented Applications
Use in a lethal PR8 influenza mouse model, with reported survival and clinical score outcomes.
Repeat intranasal administration, with measurements of anti-CBM antibody responses including IgA/IgM.
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