Humanized Antibodies Targeting Beta-Amyloid Neoepitopes
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Solution Overview
Problem
Current monoclonal antibodies, including humanized ones, often suffer from cross-reactivity with physiological proteins, leading to autoimmune side effects and uncontrollable responses, especially in treating diseases like Alzheimer's and Parkinson's, due to their inability to specifically target pathologically altered proteins without recognizing normal physiological variants.
Innovation Solution
Development of human antibodies and fragments that target neoepitopes formed due to pathological alterations, which are recognized with high affinity but not the normal physiological forms, thereby avoiding immune tolerance suppression and minimizing autoimmune reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If murine based antibodies are used for therapeutic treatment, then antibody production efficiency is improved, but human anti-mouse antibody response occurs leading to reduced therapeutic utility
Solution Approach 1:
The patent applies parameter changes by modifying the antibody's species origin from murine to human through genetic engineering. This involves changing the fundamental parameter of protein sequence identity to human levels, thereby eliminating the HAMA response while maintaining therapeutic efficacy. The humanized antibodies retain the antigen-binding capabilities of murine antibodies while presenting human sequences to the human immune system.
Solution Approach 2:
The patent uses copying by creating humanized versions of murine antibodies through genetic engineering. The variable regions that provide antigen specificity are copied and grafted onto human antibody frameworks, producing a hybrid molecule that copies the functional properties of murine antibodies while having human sequences for therapeutic compatibility.
2Measurement precision
If antibodies are designed to recognize pathological variants of proteins, then specificity for disease targets is improved, but cross-reactivity with physiological proteins may occur leading to autoimmune side effects
Solution Approach 1:
The patent applies local quality by directing antibodies to recognize specific local structural features of pathological proteins - namely neoepitopes that arise from post-translational modifications, proteolytic processing, or conformational changes. These neoepitopes represent localized structural alterations that are absent in normal physiological proteins, allowing the antibody to achieve high specificity for pathological forms without cross-reacting with normal proteins.
Solution Approach 2:
The patent inverts the traditional approach by not targeting the normal physiological protein structure, but rather targeting the abnormal pathological modifications. Instead of trying to recognize the disease-causing protein among many normal proteins, the antibody recognizes the unique pathological features that distinguish diseased from healthy states, effectively inverting the recognition strategy from 'find the abnormal among normal' to 'recognize the specific abnormal features'.
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 antibodies effectively bind to pathological forms of proteins associated with Alzheimer's disease with high specificity, reducing plaque load and improving cognitive behavior in transgenic mouse models without inducing autoimmune responses or increasing microhemorrhages.
Implementation Method 1
The antibody binds to the pathological form of the protein or the protein deposit with higher affinity than to the normal physiological form of the protein
Data Source
AI summary
Provided are novel specific binding molecules, particularly human antibodies as well as fragments, derivatives and variants thereof that recognize neoepitopes of disease-associated proteins which derive from native endogenous proteins but are prevalent in the body of a patient in a variant form and/or out of their normal physiological context. In addition, pharmaceutical compositions comprising such binding molecules, antibodies and mimics thereof and methods of screening for novel binding molecules, which may or may not be antibodies as well as targets in the treatment of neurological disorders such as Alzheimer's disease are described.