Methods of treating chronic disorders with complement inhibitors
Inventors
Francois, Cedric • Deschatelets, Pascal
Assignees
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Publication Number
US-11712460-B2
Publication Date
2023-08-01
Expiration Date
Abstract
In some aspects, the invention provides methods of treating a subject in need of treatment for a chronic complement-mediated disorder. In some aspects, the invention provides methods of treating a subject in need of treatment for a Th17-associated disorder. In some aspects, the invention provides methods of treating a subject in need of treatment for a chronic respiratory system disorder. In some aspects, the invention provides methods of administering a complement inhibitor to a subject. In some embodiments, a method of treating a subject comprises administering multiple doses of a complement inhibitor to the subject according to a dosing schedule that leverages the prolonged effect of complement inhibition in chronic respiratory disorders. In some embodiments, a subject has chronic obstructive pulmonary disease. In some embodiments, a subject has asthma.
Core Innovation
The invention relates to treating a subject in need of treatment for a chronic respiratory disorder or other chronic complement-mediated disorder by administering multiple doses of a complement inhibitor according to a dosing schedule. Successive doses are administered on average after plasma concentration decreases to no more than 10% of the maximum plasma concentration reached after the previous dose, or at intervals such that complement activation capacity is at least 50% of baseline for on average at least 3 weeks between doses.
Alternatively, successive doses are administered at intervals at least equal to 10 times the terminal plasma half-life of the complement inhibitor when administered by the same route. The method includes administering the complement inhibitor by an intravenous, intramuscular, subcutaneous, or respiratory route. The complement inhibitor comprises a nucleic acid in one independent aspect of the invention, and in another independent aspect the complement inhibitor comprises a protease that degrades C3.
The disclosure further describes long-acting compstatin analog constructs that include a peptide component and a PEG-based linker system. The PEG linker contains hydrolysis-susceptible moieties positioned between the peptide component and a (CH2CH2O)n—R moiety that includes NHS ester functionality, and hydrolysis can release the peptide from a CRM to enhance in vivo tissue penetration and/or activity.
Claims Coverage
The document excerpt provides independent claims for multi-dose treatment of chronic respiratory or other chronic complement-mediated disorders, together with disclosed construct features for long-acting compstatin analogs. Across the claims, six inventive features appear: dosing schedules based on plasma concentration decay and/or complement activation capacity recovery and/or terminal plasma half-life, defined administration routes, nucleic-acid and protease complement inhibitor modalities, and a PEG linker with CRM attachment features.
Multi-dose complementary inhibition schedule based on plasma concentration decay and/or activation recovery
Administering multiple doses of a complement inhibitor to the subject according to a dosing schedule in which successive doses are administered on average after the plasma concentration of the complement inhibitor decreases to no more than 10% of the maximum plasma concentration reached after the previous dose, at intervals such that complement activation capacity is at least 50% of baseline for on average at least 3 weeks between doses, or at intervals at least equal to 10 times the terminal plasma half-life of the complement inhibitor when administered by the same route.
Administration routes for repeated dosing
Administering the multiple doses by an intravenous, intramuscular, subcutaneous, or respiratory route.
Nucleic-acid complement inhibitor modality
The complement inhibitor comprises a nucleic acid.
Protease complement inhibitor that degrades C3
The complement inhibitor comprises a protease that degrades C3.
PEG linker with hydrolysis-susceptible moieties
A peptide component is linked by a PEG-based linker system containing hydrolysis-susceptible moieties positioned between the peptide component and a (CH2CH2O)n—R moiety that includes NHS ester functionality.
CRM attachment to peptide component
The CRM is attached to the peptide component using reactive functional groups appended to amino acids of the peptide, including Lys and Cys, with conjugation concepts including primary/secondary amines, sulfhydryl groups, maleimide, and formation of a thioether.
The claims and disclosed features center on repeated dosing of a complement inhibitor for chronic respiratory or other chronic complement-mediated disorders, with dosing intervals defined by plasma concentration decay, complement activation capacity recovery, and/or terminal plasma half-life. The complement inhibitor is characterized as either a nucleic acid or a protease that degrades C3, and the construct disclosure adds a PEG linker with hydrolysis-susceptible moieties and CRM attachment to the peptide component.
Stated Advantages
Hydrolysis-enabled release of the peptide from a CRM to enhance in vivo tissue penetration and/or activity.
Documented Applications
An example study of CA-28 in an Ascaris suum primate asthma model, with cytokine/chemokine outcomes and lung function outcomes; budesonide is mentioned in this context.
Administration contexts include nebulization/intratracheal delivery as referenced in the CA-28 example study.
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