Humanized Antibodies for Selective A-Beta Oligomer Binding
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Solution Overview
Problem
Existing antibodies fail to selectively target A-beta oligomers, which are elusive due to their conformationally-plastic and malleable structural ensemble, making them difficult to detect and treat in Alzheimer's disease and other amyloid-related diseases.
Innovation Solution
Development of humanized antibodies with specific CDR sequences that preferentially bind to A-beta oligomers, inhibiting their propagation and aggregation, while minimizing binding to monomers and fibrils.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If existing antibodies are used to target A-beta, then they bind to various forms including monomers and fibrils, but they fail to selectively bind to toxic oligomers which are present at very low concentrations
Solution Approach 1:
The antibody's binding site is engineered with specific local properties through optimized CDR sequences that recognize and bind to the unique conformational features of A-beta oligomers, distinguishing them from monomers and fibrils. This localized specificity at the binding interface enables selective detection despite the low concentration of oligomers.
Solution Approach 2:
The patent employs humanized antibodies with modified CDR sequences that change the binding parameters to preferentially recognize oligomeric structures. These parameter changes in antibody structure and binding affinity enable selective detection of oligomers at concentrations 1000-fold lower than monomers or fibrils.
2Measurement precision
If antibodies with high affinity for A-beta are developed, then they can detect oligomers, but the conformationally-plastic and malleable structure of oligomers makes them elusive and difficult to target
Solution Approach 1:
The antibody design accounts for the dynamic and conformationally-plastic nature of A-beta oligomers by creating a binding site that can adapt to various oligomeric structures. The humanized CDR sequences provide flexibility in recognizing different conformational states while maintaining high affinity binding.
Solution Approach 2:
The developed humanized antibodies possess universal binding capability across different oligomeric conformations. The CDR sequences are designed to recognize common structural features shared by various oligomeric forms, enabling the antibody to detect and bind to diverse oligomeric structures despite their conformational variability.
3Measurement precision
If humanized antibodies with specific CDR sequences are designed to preferentially bind oligomers, then selectivity improves, but the structural complexity of designing and producing these antibodies increases
Solution Approach 1:
The antibody is segmented into distinct functional regions with optimized CDR sequences that specifically recognize oligomeric structures. By dividing the binding function across multiple CDR regions (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3), each contributing to oligomer recognition, the design achieves high specificity while managing structural complexity through modular organization.
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 humanized antibodies demonstrate enhanced binding affinity and specificity for A-beta oligomers, effectively inhibiting their propagation and aggregation, providing a potential therapeutic approach for Alzheimer's disease and other amyloid-related disorders.
Implementation Method 1
humanized antibodies that are selective for Amyloid beta (A-beta or Aβ) oligomers
Data Source
AI summary
The disclosure pertains to antibodies that bind A-beta oligomers and methods of making and using said antibodies. Also provided are chimeric or humanized antibodies, including antibodies having CDRs in Table 2 and/or having a sequence as set forth in Table 4B or a sequence with at least 50% sequence identity thereto optionally wherein the CDR amino acid sequences are as set for forth in SEQ ID Nos: 74-79. Also provided are methods and uses thereof as well as kits comprising said antibodies.