Modified Botulinum Neurotoxin Receptor Binding Domain
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Solution Overview
Problem
Current Clostridial Botulinum neurotoxins (BoNTs) face limitations due to the generation of neutralizing antibodies and adverse effects associated with high doses, leading to reduced efficacy and increased risk of serious side effects, particularly in treating muscle spasms.
Innovation Solution
Modified BoNT polypeptides with specific amino acid substitutions at positions 1248 or 1249 in the receptor binding domain, such as introducing tryptophan, phenylalanine, or histidine, enhance binding affinity to neuronal receptors, allowing for reduced doses and increased specificity, thereby minimizing off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If higher doses of BoNT are used to maintain therapeutic efficacy, then treatment effectiveness is improved, but adverse effects and generation of neutralizing antibodies increase
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the BoNT heavy chain (specifically positions 1248-1250) to alter the toxin's binding properties. This enables the toxin to achieve the same therapeutic effect at lower doses, thereby reducing adverse effects while maintaining treatment effectiveness
Solution Approach 2:
The patent applies local quality by making specific localized modifications to the receptor binding domain of the BoNT (positions 1248-1250 of the heavy chain). These targeted amino acid substitutions enhance neuronal specificity without affecting other functional domains of the toxin, allowing reduced dosing while maintaining efficacy
2Reliability
If higher doses of BoNT are used to ensure therapeutic efficacy, then treatment effectiveness is improved, but the generation of neutralizing antibodies increases
Solution Approach 1:
The patent modifies the amino acid parameters of the BoNT heavy chain (positions 1248-1250) to create a variant that maintains immunogenicity for therapeutic effect while reducing the dose required. Lower doses result in reduced immune system activation and fewer neutralizing antibodies being generated
3Object-affected harmful factors
If BoNT with higher neuronal specificity is developed, then off-target effects are reduced, but the complexity of toxin modification increases
Solution Approach 1:
The patent applies local quality by implementing focused amino acid substitutions only in the receptor binding domain (positions 1248-1250 of the heavy chain). This localized approach enhances neuronal specificity and reduces off-target effects while keeping the overall toxin structure and production methodology relatively simple
Solution Approach 2:
The patent uses parameter changes through specific amino acid substitutions (e.g., positions 1248-1250) to improve neuronal binding affinity. These targeted parameter modifications achieve better specificity without requiring complex structural redesign or multiple domain alterations
Data Source
AI summary
Disclosed herein are modified Clostridial Botulinum neurotoxin (BoNT) polypeptides with a modified receptor binding domain of Clostridial Botulinum serotype B, comprising one or more substitution mutations at positions corresponding 1248 or 1249 in serotype B, strain 1. Specific substitution mutations include I1248F, I1248Y, I1248H, I1248W, V1249W, V1249F, V1249Y, V1249H, I1248W/V1249F, I1248W/V1249Y, I1248W/V1249H, I1248F/V1249Y, I1248F/V1249H, I1248Y/V1249H, I1248F/V1249W, I1248Y/V1249W, I1248H/V1249W, I1248Y/V1249F, I1248H/V1249F, or I1248H/V1249Y. Other substitution mutations are also disclosed. Isolated modified receptor binding domains, chimeric molecules, pharmaceutical compositions, and methods of using the same are also disclosed.