Monomeric Protein Tailpiece Engineering for IVIG Stability
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Solution Overview
Problem
Current treatments for autoimmune and inflammatory diseases, such as IVIG, face challenges including limited global supply, high production costs, and adverse events due to excessive protein loading, with less than 5% of injected IVIG being therapeutically active, and a reliance on human donors for manufacture.
Innovation Solution
Development of a protein comprising two chimeric polypeptide chains with an Fc receptor binding portion and an immunoglobulin tailpiece region, adapted to inhibit polymerization, allowing for monomeric form stability and enhanced binding to sialic acid-dependent receptors like DC-SIGN and SIGLEC-1, reducing adverse effects and increasing therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If oligomeric structures are formed to increase avidity of binding, then binding strength to Fc-receptors is improved, but polymerisation occurs which is unwanted for monomeric protein stability
Solution Approach 1:
The Fc receptor binding portion is divided into two separate chimeric polypeptide chains, each containing an IgG heavy chain constant region. These chains are designed to remain separate (monomeric) rather than forming oligomeric structures, thus maintaining monomeric stability while still providing Fc receptor binding capability through the engineered chimeric structure
Solution Approach 2:
The amino acid sequence of the tailpiece region is modified with specific adaptations that change the polymerisation parameters of the protein. These sequence changes prevent intermolecular interactions that would lead to oligomer formation, thereby stabilizing the monomeric form while preserving therapeutic function
2Reliability
If IVIG is administered to achieve therapeutic effects, then autoimmune and inflammatory diseases are treated, but excessive protein loading causes adverse events
Solution Approach 1:
The invention extracts and isolates the essential therapeutic Fc receptor binding portion of IgG into a simplified chimeric structure. By taking only the necessary functional elements (Fc region with engineered tailpiece) and removing the bulk protein mass of full IVIG, the treatment achieves therapeutic effects at lower protein loads, reducing adverse events associated with excessive protein administration
Solution Approach 2:
The chimeric protein is designed as a simplified, production-efficient molecule that can be manufactured more readily than full IVIG. The streamlined structure allows for scalable production with fewer constraints, making effective treatment more accessible while using smaller, controlled doses to avoid protein loading toxicity
3Reliability
If Fc receptor binding portion is engineered for high avidity, then anti-inflammatory function is improved, but complement cascade activation occurs which is harmful
Solution Approach 1:
The chimeric polypeptide chains are engineered with specific local modifications in the tailpiece region that create distinct functional zones. The amino acid adaptations are localized to specific residues that control polymerisation and receptor binding, while other regions are designed to avoid complement activation. This localized engineering allows high avidity binding without the harmful side effect of complement cascade activation
Data Source
AI summary
Provided are proteins comprising two chimeric polypeptide chains; wherein each chimeric polypeptide chain comprises an Fc receptor binding portion comprising two immunoglobulin G heavy chain constant regions; and an immunoglobulin tailpiece region. The amino acid sequence and glycosylation of the tailpiece region of the proteins is adapted, as compared to the sequence and glycosylation of wild-type immunoglobulin, to inhibit polymerisation of the protein. The adaptation of the amino acid sequence may be the loss of a cysteine residue, for example the cysteine residue corresponding to residue 248 of SEQ ID NO: 1. The proteins may be used in intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) therapy. They may be used in the prevention or treatment of a disease mediated through binding of sialic acid-dependent receptors. Proteins of the invention may be used in the prevention and/or treatment of autoimmune or inflammatory diseases. The proteins may be conjugated to an immune modulator, and in such cases are suitable for vaccine use.