Glycoengineered Polypeptides for Targeted IgA1 Immune Complex Depletion
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Solution Overview
Problem
Current therapies for IgA nephropathy, such as blood pressure medications and non-specific B-cell directed therapies like Atacicept, fail to directly target and reduce IgA1 levels, galactose-deficient IgA1, anti-gd-IgA1 autoantibodies, or immune complexes, leading to prolonged treatment duration, lack of specificity, and undesirable side effects.
Innovation Solution
Glycoengineered polypeptides that specifically bind to target antibodies, such as IgA1, gd-IgA1, or anti-gd-IgA1 autoantibodies, and endocytic receptors, inducing internalization and degradation through glycans, thereby reducing and removing these pathogenic components.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-specific B-cell directed therapies like Atacicept are used, then B cells are depleted, but this causes non-specific depletion of all antibodies including beneficial ones, leading to unwanted side effects and prolonged treatment duration
Solution Approach 1:
The therapy transitions from non-specific B-cell depletion to specific targeting of pathogenic IgA1 immune complexes through glycoengineered polypeptides that recognize and bind to galactose-deficient IgA1 structures. This local quality approach eliminates harmful factors (pathogenic IgA1) while preserving beneficial factors (other antibodies), thereby reducing unwanted side effects and improving therapeutic specificity.
2Productivity
If non-specific B-cell directed therapies are used, then disease treatment is attempted, but rapid response is not achieved due to lack of targeting of disease-causing components
Solution Approach 1:
The invention extracts and removes the specific pathogenic component (galactose-deficient IgA1) from the complex immune system through glycoengineered polypeptides that specifically bind to and eliminate only the harmful IgA1 structures. This extraction approach enables rapid response by directly removing the disease-causing agent without the delays associated with non-specific B-cell depletion therapies.
3Quantity of substance
If current therapies are used, then some relief is provided, but they do not directly reduce IgA1 levels or immune complexes comprising the same
Solution Approach 1:
The glycoengineered polypeptides serve as intermediary agents that directly interact with and remove pathogenic IgA1 immune complexes. These polypeptides mediate the reduction of IgA1 levels by binding to galactose-deficient IgA1 structures and facilitating their elimination, providing direct targeting capability that current therapies lack.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The glycoengineered polypeptides provide rapid, specific, and durable responses with fewer side effects, effectively depleting target antibodies and immune complexes, offering improved treatment outcomes for IgA-associated diseases.
Implementation Method 1
a first moiety that binds to a target antibody
Implementation Method 2
inducing internalization and degradation of the target antibody
Implementation Method 3
inducing internalization and degradation of the target antibody
Implementation Method 4
a second moiety comprising one or more glycans that bind to an endocytic receptor
Data Source
AI summary
Provided herein are glycoengineered polypeptides comprising a first moiety comprising one or more peptides that specifically binds to a target antibody (e.g., an IgA1 or an immune complex comprising the same, a gd-IgA1 or an immune complex comprising the same, or an anti-gd-IgA1 autoantibody or an immune complex comprising the same) and a second moiety comprising one or more glycans conjugated to the first moiety at one or more glycosylation sites. Also provided herein are nucleic acid sequence encoding provided glycoengineered polypeptides. Further provided herein are compositions comprising glycoengineered polypeptides and/or nucleic acids encoding the same, as well as methods of making and using the same.