Chimeric Protein Bacterial Delivery for Parasite Immunization
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Solution Overview
Problem
Current methods for delivering anti-infective therapeutics and vaccines face challenges in effectively targeting mucosal surfaces and achieving sustained immune responses, particularly for infectious diseases and parasites, due to limitations in antigen secretion and stability, and the inability to prevent degradation of effector proteins by proteases.
Innovation Solution
Development of novel chimeric proteins and bacterial delivery vectors that express and secrete anti-parasitic or anti-infectious agent proteins, using attenuated or non-pathogenic bacteria to stimulate immune responses and deliver therapeutic molecules directly to the site of infection, while co-expressing protease inhibitors to enhance stability and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If live attenuated bacteria are used to deliver heterologous antigens, then immune response stimulation is improved, but antigen secretion quantity and stability deteriorate
Solution Approach 1:
The patent modifies bacterial secretion system parameters by engineering the type I secretion system components (hlyB, hlyD, tolC genes) to optimize antigen secretion efficiency. This involves changing the functional parameters of the secretion machinery to overcome the limitation of insufficient antigen secretion while maintaining bacterial viability and immune stimulation capability.
Solution Approach 2:
The patent creates composite secreted proteins by fusing heterologous antigens with bacterial secretion signals and stability domains. This composite structure enables the antigen to be efficiently secreted by the bacterial type I secretion system while maintaining stability and immunogenicity, thereby resolving the contradiction between secretion quantity and stability.
2Ease of manufacture
If secreted proteins are used in live bacterial vectors, then antigen delivery is improved, but protein degradation by proteases worsens
Solution Approach 1:
The patent introduces protease inhibitors as intermediary molecules that mediate between the secreted antigen and environmental proteases. These inhibitors protect the antigen from degradation by forming a protective complex, allowing the antigen to maintain stability in the protease-rich environment while still being delivered effectively to the target site.
Solution Approach 2:
The patent changes the chemical composition parameters of the secreted protein complex by co-secreting protease inhibitors alongside the antigen. This modification of the protein complex composition prevents proteolytic degradation while maintaining the antigen's immunogenic properties and delivery efficiency.
3Productivity
If type I secretion system is used for antigen delivery, then secretion efficiency is improved, but secretion capacity limitations worsen
Solution Approach 1:
The patent optimizes the functional parameters of the type I secretion system by engineering the hlyB, hlyD, and tolC genes to enhance secretion capacity. This involves modifying the kinetic and thermodynamic parameters of the secretion process to overcome the natural limitations of the system while maintaining its high efficiency characteristics.
Solution Approach 2:
The patent creates a dynamic secretion system that can adapt to different antigen loads and secretion demands. By engineering the secretion machinery components, the system gains flexibility in handling varying quantities of heterologous antigens, overcoming the rigid capacity limitations of the wild-type type I secretion system.
Data Source
AI summary
Chimeric proteins are expressed, secreted or released by a bacterium to immunize against or treat a parasite, infectious disease or malignancy. The delivery vector may also be attenuated, non-pathogenic, low pathogenic, or a probiotic bacterium. The chimeric proteins include chimeras of, e.g., phage coat and/or colicin proteins, bacterial toxins and/or enzymes, autotransporter peptides, lytic peptides, multimerization domains, and/or membrane transducing (ferry) peptides. The active portion of the immunogenic chimeric proteins can include antigens against a wide range of parasites and infectious agents, cancers, Alzheimer's and Huntington's diseases, and have enhanced activity when secreted or released by the bacteria, and/or have direct anti-parasite or infectious agent activity. The activity of the secreted proteins is further increased by co-expression of a protease inhibitor that prevents degradation of the effector peptides. Addition of an antibody binding or antibody-degrading protein further prevents the premature elimination of the vector and enhances the immune response.