Engineered Microorganism Inducing Systemic Cellular Immune Response
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Solution Overview
Problem
Current tumor vaccines fail to induce a strong systemic cellular immune response and often result in systemic tolerance or Th2-type immune responses, which are inadequate for effective tumor therapy, due to the toxicity of native toxins and the attenuated adjuvant effect of detoxified toxins.
Innovation Solution
A microorganism is engineered to carry nucleotide sequences coding for antigens and protein toxins, including a transport system for surface expression or secretion, enabling the production of toxin-antigen fusion proteins that can be secreted or expressed on the surface, thereby inducing a systemic cellular immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native toxins are used as adjuvants in vaccines, then strong immune response is induced, but high toxicity prevents human use
Solution Approach 1:
The toxin is divided into separate functional domains (e.g., B-subunit for binding, A-subunit for enzymatic activity). The B-subunit is used as an adjuvant to induce immune response without the toxic enzymatic activity of the A-subunit, thereby separating the beneficial immunogenic function from the harmful toxic function.
Solution Approach 2:
The toxic toxin is detoxified through genetic engineering or chemical modification while preserving its ability to bind to host cells and induce immune response. The detoxified toxin retains the beneficial adjuvant effect while the harmful toxicity is eliminated or significantly reduced.
2Object-affected harmful factors
If detoxified toxins are used as adjuvants, then toxicity is reduced, but adjuvant effect is attenuated
Solution Approach 1:
Different regions or domains of the toxin molecule are engineered to have different properties. The binding domain (e.g., B-subunit) is optimized for high affinity and immunogenicity, while the catalytic domain (e.g., A-subunit) is modified or removed to eliminate toxicity. This local differentiation allows the adjuvant effect to be maintained while toxicity is reduced.
Solution Approach 2:
The vaccine composition is engineered as a composite system combining detoxified toxin subunits with other immunogenic components or adjuvants. This composite approach compensates for any attenuation of the adjuvant effect while maintaining the safety profile of the detoxified toxin.
3Reliability
If fusion proteins of toxins and antigens are produced, then adjuvant effect is enhanced, but complexity of production increases
Solution Approach 1:
The toxin gene and antigen gene are merged into a single fusion gene construct that can be expressed as a single polypeptide chain. This fusion protein simultaneously provides the adjuvant effect from the toxin portion and the specific antigenicity from the antigen portion, simplifying the vaccine formulation while enhancing the immune response.
Solution Approach 2:
The fusion protein design allows a single molecular entity to perform multiple functions: the toxin domain provides adjuvant activity to enhance immune response, while the antigen domain provides specific target recognition. This multi-functionality reduces the need for separate components and simplifies production.
Data Source
AI summary
A Escherichia, Salmonella, Yersinia, Vibrio, Listeria, Shigella, or Pseudomonas bacterium that has the following components: (I) a polynucleotide encoding a heterologous antigenic determinant that induces a CTL response against a tumor cell; (II) a polynucleotide encoding a heterologous protein toxin or toxin subunit; and (III) (a) a polynucleotide encoding a transport system that expresses the products of (I) and (II) on the outer surface of the bacterium or that secretes products of (I) and (II) from the bacterium; and (IV) a polynucleotide that activates the expression of one or more of (I). (II), and/Or (III) in the bacterium wherein polynucleotides (I), (II), (III) and (IV) are different from each other and polynucleotides (I), (II) and (III) encode proteins that are different from each other.