p110-delta inhibitors treat and prevent autoimmunity while sparing the ability to mount an immune response to exogenous immunogens
Inventors
Cambier, John • FRANKS, Elizabeth
Assignees
University of Colorado Boulder • National Institutes of Health NIH
Publication Number
US-11701361-B2
Publication Date
2023-07-18
Expiration Date
2039-01-07
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Methods of using a phosphoinositide 3-kinase p110-delta inhibitor to treat, delay the onset, or slow the progression of an autoimmune disease or disorder in a subject, without suppressing the subject's B cell responses to exogenous antigens or rendering the subject immunocompromised, as well as pharmaceutical compositions containing phosphoinositide 3-kinase p110-delta inhibitors in amounts suitable for convenient and accurate administration within these therapeutic methods.
Core Innovation
This invention relates to methods of using a phosphoinositide 3-kinase p110-delta (PI3K-p110δ) inhibitor to treat, delay the onset, or slow the progression of an autoimmune disease or disorder in a subject, without suppressing the subject's B cell responses to exogenous antigens or rendering the subject immunocompromised. The invention also comprises pharmaceutical compositions containing phosphoinositide 3-kinase p110-delta inhibitors suitable for convenient and accurate administration within these therapeutic methods.
The inventors discovered that administration of low doses of PI3K-p110δ inhibitors compensates for failed PI3K pathway regulation, thereby delaying development of autoimmunity in a murine model of type 1 diabetes while preserving immunocompetence. Specifically, low dose p110δ inhibition selectively inhibits participation in autoimmunity of autoreactive B cells that have lost anergy due to defective PI3K pathway regulation and does not affect in vitro or in vivo T cell responses. Thus, this disclosure provides methods of treating autoimmune disorders by modifying B cell antigen receptor signaling to prevent or significantly reduce responses to self or endogenous antigens while ensuring protective immunological responses against exogenous pathogens.
The problem addressed by this invention is the unmet need for effective treatments of autoimmune diseases and disorders that do not cause immunocompromise. Existing therapies such as B cell depletion therapies can leave patients susceptible to infection and prevent proper response to immunization. The invention solves this problem by administering PI3K-p110δ inhibitors in dosages and schedules that treat or delay autoimmune disease while sparing B cell responses to exogenous antigens, thus maintaining the ability of the subject to mount immune responses to external immunogens without suppression of the immune system.
Claims Coverage
The claims define several inventive features centered on methods and dosages for treating autoimmune diseases using PI3K-p110δ inhibitors that do not reduce immune response to exogenous immunogens.
Treatment method using PI3K-p110δ inhibitor without reducing immune response to exogenous immunogens
A method of treating or delaying onset or slowing progression of an autoimmune disease or disorder in a subject by administering a therapeutically effective amount of a phosphoinositide 3-kinase p110-delta (PI3K-p110δ) inhibitor to the subject at a dosage that does not reduce immune response to exogenous immunogens.
Use of idelalisib as the PI3K-p110δ inhibitor
The method comprises using idelalisib as the PI3K-p110δ inhibitor for the treatment.
Idelalisib administration dosage range
Idelalisib is administered at a dosage between about 0.23 mg/kg/day and about 3.6 mg/kg/day, including subranges from about 0.45 mg/kg/day to about 1.8 mg/kg/day, about 0.9 mg/kg/day to about 1.8 mg/kg/day, or about 1.8 mg/kg/day to about 3.6 mg/kg/day, and specific dosages of about 0.9 mg/kg/day or about 1.8 mg/kg/day.
Autoimmune diseases treatable by the method
The autoimmune disease or disorder that can be treated includes autoimmune diabetes mellitus (type 1 diabetes mellitus; TID), systemic lupus erythematosus, autoimmune thyroiditis, rheumatoid arthritis, psoriasis, and multiple sclerosis, with exemplary treatment of type 1 diabetes mellitus (TID).
The claims collectively cover methods of treating various autoimmune diseases by administering therapeutically effective PI3K-p110δ inhibitors, particularly idelalisib, at defined dosages that do not impair immune responses to external immunogens.
Stated Advantages
Low dose PI3K-p110δ inhibitor treatment delays development of autoimmunity while preserving immunocompetence and responses to immunization.
Selective inhibition of autoreactive B cells that have lost anergy without affecting T cell responses.
Maintains ability to mount protective immune responses to exogenous antigens, avoiding immunocompromise.
Unexpected efficacy and reduced toxicity in treated subjects.
Documented Applications
Treatment, delay of onset, or slowing progression of autoimmune diseases or disorders including autoimmune diabetes mellitus (type 1 diabetes mellitus; TID), systemic lupus erythematosus, autoimmune thyroiditis, rheumatoid arthritis, psoriasis, and multiple sclerosis.
Treatment of subjects displaying reduced activity of phosphatase and tensin homolog (PTEN) or SH-2-containing inositol phosphatase SHIP-1 in B cells.
Use in therapeutic, prophylactic, in vitro, in situ, and in vivo diagnosis or treatment of pathological autoimmune conditions mediated by PI3 kinase, especially via selective inhibition of the p110 delta isoform.
Interested in licensing this patent?