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Publication Number
US-11034775-B2
Publication Date
2021-06-15
Expiration Date
Abstract
The present disclosure involves biologically active proteins termed cysteine-optimized multimerizing stradomers. Thus, the present disclosure provides compositions and methods providing anti-autoimmune and anti-inflammatory activities, useful in the treatment of diseases and conditions including autoimmune diseases, inflammatory diseases, or infectious diseases.
Core Innovation
The invention relates to cysteine-optimized multimerizing stradomer units derived from GL-2045, where the multimerizing stradomer is composed of at least two stradomer unit monomers. Each monomer comprises an IgG1 Fc domain monomer including an IgG1 hinge, IgG1 CH2, and IgG1 CH3 domain, together with an IgG2 hinge multimerization domain monomer.
The concept is to introduce serine mutations at cysteine residues located in the IgG1 Fc domain monomer or the IgG2 hinge multimerization domain monomer. Free cysteines can form undesirable intermolecular disulfides, and the work focuses on mutating or deleting non-structural cysteines to reduce unwanted oxidation/aggregation while substantially maintaining multimerization and Fc-function.
The document provides mapping of cysteine-containing positions for GL-2045 and discusses disulfide bond analysis and multimerization/performance assessment for the cysteine-optimized variants. Functional results are asserted through disulfide bond analysis, multimer analysis including SDS-PAGE/non-reducing SDS-PAGE multimer analysis, SEC-MALS and dynamic light scattering, and binding/functional readouts including CDC inhibition and FcγRIIIA binding.
The cysteine-optimized multimerizing stradomers are stated to provide immune suppression or immune tolerance with modulation of complement and Fc receptor-related activities, including CDC and ADCC/ADCP-associated mechanisms. Broad therapeutic use is described for inflammatory, autoimmune, and infectious diseases, including administration routes and formulation options.
Claims Coverage
The independent claims presented in the provided material cover one main invention: a cysteine-optimized multimerizing stradomer unit formed from at least two stradomer unit monomers with IgG1 Fc domain structure and an IgG2 hinge multimerization domain, combined with serine substitutions at specified cysteine positions in SEQ ID NO: 10. The associated inventive features are centered on the location and presence of serine mutations at defined cysteine residues and the multimerizing stradomer unit architecture.
Cysteine-optimized multimerizing stradomer unit architecture with IgG1 Fc and IgG2 hinge multimerization domain
A cysteine-optimized multimerizing stradomer unit comprising at least two stradomer unit monomers, where each monomer comprises an IgG1 Fc domain monomer comprising an IgG1 hinge, IgG1 CH2, and IgG1 CH3 domain and an IgG2 hinge multimerization domain monomer.
Serine mutation at selected cysteine residues in IgG1 Fc or IgG2 hinge at positions 5, 11, 14, 152, 210, or 243
One or both of the at least two stradomer unit monomers comprise at least one serine mutation at a cysteine residue in the IgG1 Fc domain monomer or the IgG2 hinge multimerization domain monomer at position 5, 11, 14, 152, 210, or 243, or a combination thereof, of SEQ ID NO: 10.
Overall, claim coverage focuses on a multimerizing stradomer built from IgG1 Fc (hinge/CH2/CH3) plus an IgG2 hinge multimerization domain, together with serine mutations at specified cysteine residues in the IgG1 Fc domain or IgG2 hinge multimerization domain relative to SEQ ID NO: 10.
Stated Advantages
Reduce unwanted oxidation/aggregation while substantially maintaining multimerization and Fc-function.
Show increased multimerization compared with a stradomer comprising SEQ ID NO: 10.
Provide immune suppression or immune tolerance with modulation of CDC and FcγRIIIA-related activities.
Documented Applications
Therapeutic use for inflammatory diseases, autoimmune diseases, and infectious diseases, including immune suppression/tolerance and potential modulation of complement and Fc-receptor associated functions (including CDC and ADCC/ADCP-associated mechanisms).
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