Fusion proteins of human protein fragments to create orderly multimerized immunoglobulin Fc compositions with enhanced complement binding
Inventors
Block, David S. • Olsen, Henrik
Assignees
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Publication Number
US-12122836-B2
Publication Date
2024-10-22
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. The invention involves stradomers that increase multimerization and bind preferentially to complement and that are useful in the treatment and prevention of disease.
Core Innovation
The invention relates to a peptide homodimer comprising an IgG1 Fc domain and at least one multimerization domain, where the IgG1 Fc domain is defined by the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3 with point mutations consisting of S267E, H268F, N297A, and S324T based on the EU index of the IgG1 Fc domain. The peptide homodimer retains binding to C1q.
The disclosed embodiments include multimerization domains selected from an IgG2 hinge, an isoleucine zipper, or a GPP domain, and the domain is capable of multimerizing the peptide homodimers. In additional embodiments, the multimers of the peptide homodimers form high-order multimers.
The document further states that the peptide homodimer preferentially binds complement compared with Fcb3RI, Fcb3RIIa, Fcb3RIIb, and/or Fcb3RIII. In at least one embodiment, the peptide homodimer binds C1q and inhibits CDC.
Claims Coverage
The independent claim covers an Fc-bearing peptide homodimer with an IgG1 Fc domain carrying the specific point mutations S267E, H268F, N297A, and S324T, at least one multimerization domain, and retained binding to C1q. The claim set also includes dependent refinements for multimerization domain choice, high-order multimer formation, preferential complement binding, and CDC inhibition.
C1q-retaining IgG1 Fc point-mutated peptide homodimer
A peptide homodimer comprising at least one IgG1 Fc domain comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3 with point mutations consisting of S267E, H268F, N297A, and S324T based on the EU index of the IgG1 Fc domain, and at least one multimerization domain, wherein the peptide homodimer retains binding to C1q.
Defined multimerization domain selection for peptide homodimer
A peptide homodimer in which the multimerization domain is chosen from an IgG2 hinge, an isoleucine zipper, or a GPP domain, and the domain is capable of multimerizing the peptide homodimers.
High-order multimer formation
A peptide homodimer in which the multimers of the peptide homodimers form high-order multimers.
Preferential complement binding over Fcb3 receptors
A peptide homodimer that preferentially binds complement compared with Fcb3RI, Fcb3RIIa, Fcb3RIIb, and/or Fcb3RIII.
C1q binding with CDC inhibition
A peptide homodimer that binds C1q and inhibits CDC.
The claims center on a peptide homodimer containing an IgG1 Fc domain with the specified EU-index point mutations and at least one multimerization domain, while retaining C1q binding. Dependent claims further specify multimerization domain options, high-order multimers, preferential complement binding over specified Fcb3 receptors, and inhibition of CDC.
Stated Advantages
Retains binding to C1q.
Preferentially binds complement compared with Fcb3RI, Fcb3RIIa, Fcb3RIIb, and/or Fcb3RIII.
Inhibits CDC.
Documented Applications
C1q binding with inhibition of CDC in a complement-related context.
Use of peptide homodimers that preferentially bind complement versus Fcb3 receptors.
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