SM Crosslinked Peptide-KLH Conjugates for Alzheimer's Immunization

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Solution Overview

Problem

Existing immunization methods for amyloid diseases, such as Alzheimer's, often rely on crosslinking agents that do not adequately enhance the immune response, leading to insufficient immunization and potential side effects, with most prior art neglecting the importance of the crosslinking agent in conjugate formation.

Innovation Solution

The use of maleimidobutyric acid N-hydroxysuccinimide ester (SM) as a crosslinking agent to create CysAβ(33-40) peptide-keyhole limpet hemocyanin (KLH) conjugates, which significantly improves immune response specificity and strength, reducing the required doses and minimizing side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional crosslinking agents are used to form peptide-transport protein conjugates, then the conjugate can be generated, but the immune response is insufficient and lacks specificity

Engineering Contradiction:
Improveimmune response qualityVSAvoidconjugate formation process
Core Design Contradiction:
ReliabilityVSEase of manufacture

Solution Approach 1:

The patent changes the chemical parameters of the crosslinking agent, selecting maleimidobutyric acid N-hydroxysuccinimide ester (SM) over conventional agents like SPDP or LPA. This parameter change in the crosslinking chemistry results in superior conjugates that elicit more specific and potent immune responses against Aβ40, while maintaining ease of conjugate formation through standard bioconjugation protocols

Inventive Principle:
Principle #35Parameter changes

Solution Approach 2:

The patent uses the crosslinking agent SM as an intermediary that mediates the binding between the CysAβ(33-40) peptide and the KLH transport protein. This intermediary forms a stable conjugate structure that presents the peptide antigen in a manner that optimizes immune recognition, thereby improving immune response quality without complicating the manufacturing process

Inventive Principle:
Principle #24Intermediary (Mediator)

2Reliability

If higher doses of immunogenic conjugate are used to enhance immune response, then immunization efficacy improves, but side effects increase

Engineering Contradiction:
Improveimmunization efficacyVSAvoidside effects
Core Design Contradiction:
ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the parameters of the conjugate structure through the use of crosslinking agent SM, creating a conjugate with optimized immunogenic properties. This parameter change in conjugate structure allows for higher efficacy at lower doses, as the SM-crosslinked conjugate presents the Aβ40 peptide in a form that elicits more potent and specific antibody responses, thereby reducing the dose required and minimizing side effects

Inventive Principle:
Principle #35Parameter changes

3Adaptability or versatility

If broad-spectrum antibodies are generated to cover multiple Aβ variants, then coverage is improved, but specificity for Aβ40 is reduced and anti-Aβ42 antibodies increase

Engineering Contradiction:
Improveantibody coverageVSAvoidantibody specificity
Core Design Contradiction:
Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The patent applies local quality by using the crosslinking agent SM to create a conjugate that specifically presents the Aβ40 peptide sequence (CysAβ(33-40)) in a manner that elicits antibodies specifically targeting Aβ40. This local optimization of the conjugate structure at the peptide-transport protein interface ensures that the immune response is highly specific for Aβ40, avoiding the generation of broad-spectrum antibodies that would include anti-Aβ42 responses

Inventive Principle:
Principle #3Local quality

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 SM-crosslinked conjugates generate a specific and potent immune response against Aβ40, reducing anti-Aβ42 antibody production, thereby enhancing immunization efficacy while minimizing side effects and reducing the necessary immunogenic conjugate doses.

Implementation Method 1

maleimidobutyric acid N-hydroxysuccinimide ester (hereinafter, SM), a heterobifunctional crosslinking agent, in which each molecule thereof binds a peptide to the transport protein

Methodology Applied
Scientific EffectChemical Bonding: Chemical Bonding

Data Source

PatentUS20220184178A1Amyloid conjugate and uses and methods thereof
Publication Date: 2022.06.16 ARACLON BIOTECH

AI summary

A composition includes aluminum hydroxide gel and a conjugate of at least one CysA13(33-40) peptide linked to the keyhole limpet hemocyanin (KLH). Maleimidobutyric acid Nhydroxysuccinimide ester (SM) serves as cross-linking agent. The composition can produce an effective and specific immune response against Aβ40. The antibodies produced are specific for Aβ40 without significantly binding to Aβ42. The composition can increase the response against Aβ40 compared with the response produced by other conjugates that include CysAβ(33-40) peptide and KLH, and are bound or conjugated by other crosslinking agents.55139597