Fusion proteins of natural human protein fragments to create orderly multimerized immunoglobulin Fc compositions
Inventors
Block, David S. • Olsen, Henrik
Assignees
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Publication Number
US-12084482-B2
Publication Date
2024-09-10
Expiration Date
Abstract
The current invention involves a series of fully recombinant multimerized forms of immunoglobulin Fc which thereby present polyvalent immunoglobulin Fc to immune cell receptors. The fusion proteins exist as both homodimeric and highly ordered multimeric fractions, termed stradomers. In comparison to the homodimeric fraction, purified multimeric stradomers have higher affinity and avidity for FcγRs with slower dissociation and are useful in the treatment and prevention of disease. The current invention demonstrates that directly linking IgG1 Fc regions to multimerization domains leads to enhanced multimerization and biological activity.
Core Innovation
The invention relates to fixed Fc/stradomer reagents provided as pharmaceutical compositions for treating an inflammatory disease or autoimmune disease in a subject in need thereof. The compositions comprise a multimerized compound comprising two or more homodimeric stradomer units. Each homodimeric stradomer unit includes two stradomer unit monomers, where the monomer sequences are defined as amino acid residues 21-264 of SEQ ID NO:4 or as sequences of SEQ ID NO:2 directly linked at its carboxy terminus to SEQ ID NO:3.
The described multimerized compounds include higher order multimers formed from the homodimeric stradomer units, with options for the number of homodimeric stradomer units. The document frames stradomers as multimeric fixed Fc reagents used across inflammatory, autoimmune, and related infectious and transplant-associated conditions, including autoimmune hematoimmunological processes and alloimmune/autoimmune thrombocytopenia.
The disclosure also describes the use of stradomers in immunological assays as immunological assay controls to distinguish Fab-specific effects from Fc-FcγR effects. Stradomers are described as Fc-blocking reagents in assays, including flow cytometry, and as endotoxin-binding stradomer complexes to enable endotoxin removal. The document additionally reports binding and avidity analyses involving Fcγ receptors and SIGN-R1, and describes in vivo efficacy in preventive models and experimental autoimmune disease models.
Claims Coverage
The independent claims cover two inventive approaches to treating inflammatory or autoimmune diseases using pharmaceutical compositions containing a multimerized compound built from two or more homodimeric stradomer units, with defined monomer sequence architecture. Across the independent claims, the inventive features focus on fixed Fc/stradomer multimer structure, monomer sequence definition, and the administration-based treatment context for inflammatory or autoimmune disease.
Treating inflammatory or autoimmune disease with multimerized homodimeric stradomer composition
Administering an effective amount of a pharmaceutical composition comprising a multimerized compound comprising two or more homodimeric stradomer units, wherein each homodimeric stradomer unit comprises two stradomer unit monomers, and wherein each stradomer unit monomer comprises amino acid residues 21-264 of SEQ ID NO:4.
Treating inflammatory or autoimmune disease with homodimeric stradomer composition defined by direct carboxy-terminal linking
Administering an effective amount of a pharmaceutical composition comprising a multimerized compound comprising two or more homodimeric stradomer units, wherein each homodimeric stradomer unit comprises two stradomer unit monomers, each stradomer unit monomer comprising the amino acid sequence of SEQ ID NO:2 directly linked at its carboxy terminus to the amino acid sequence of SEQ ID NO:3.
Overall, the claim coverage is directed to treating inflammatory or autoimmune disease by administering pharmaceutical compositions containing multimerized compounds composed of two or more homodimeric stradomer units, with two alternative monomer definitions: (i) a monomer comprising amino acid residues 21-264 of SEQ ID NO:4, or (ii) a monomer defined by direct carboxy-terminal linking of SEQ ID NO:2 and SEQ ID NO:3. The provided dependent claim concepts add higher order multimers and constrain the number of homodimeric stradomer units and/or tie the treated indication to diseases associated with human IVIG.
Stated Advantages
Improved FcγR binding with higher affinity/avidity and slower dissociation relative to prior constructs.
Increased multimer formation.
Increased biological activity versus prior constructs containing extraneous sequences.
Comparable preventative protection in an idiopathic thrombocytopenia purpura model relative to IVIG.
Synergy with prednisolone in collagen induced arthritis.
Enhanced receptor binding kinetics as described in the document.
Additional utility as Fc-blocking reagents in immunoassays and as endotoxin-binding/removal tools.
Provides pharmaceutical compositions for treating a wide range of inflammatory and autoimmune diseases in a subject in need thereof.
Uses stradomers as immunological assay controls to distinguish Fab-specific effects from Fc-FcγR effects.
Provides stradomers as Fc-blocking reagents in assays such as flow cytometry.
Provides endotoxin-binding stradomer complexes to enable endotoxin removal.
Documented Applications
Treatment of inflammatory and autoimmune diseases, including conditions enumerated in the dependent claims.
Preventative protection in an idiopathic thrombocytopenia purpura (ITP) mouse model.
Efficacy in collagen induced arthritis and described synergy with prednisolone.
Use as Fc-blocking reagents in immunological assays.
Endotoxin-binding/removal utility.
Immunological assay control use of stradomers to distinguish Fab-specific versus Fc-FcγR effects.
Fc-blocking reagent use of stradomers in assays including flow cytometry.
Endotoxin-binding stradomer complexes to enable endotoxin removal.
Treatment of inflammatory disease or autoimmune disease across a broad set of enumerated conditions including autoimmune hematoimmunological processes, autoimmune thrombocytopenia, autoimmune neutropenia, autoimmune hemolytic anemia, and infectious/transplant-associated related conditions.
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