MIP DNA Vaccine Combined with LAG-3 Blockade
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Solution Overview
Problem
DNA vaccines using mini-intronic plasmids (MIPs) are less effective than conventional plasmid DNA vaccines in treating tumors due to increased expression of the immune checkpoint protein LAG-3 on CD8+ T cells, which inhibits the immune response, and the relationship between DNA vector types and immune checkpoint pathways is not well understood.
Innovation Solution
Administering a mini-intronic plasmid (MIP) DNA vaccine that encodes an antigen and includes a bacterial origin of replication and selectable marker within an intron, combined with a LAG-3 immune checkpoint protein blocking agent to reduce immunoinhibitory effects and enhance antigen-specific CD8+ T cell activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If mini-intronic plasmid (MIP) DNA vaccine is used to encode antigen, then antigen expression is improved, but LAG-3 immune checkpoint protein expression on CD8+ T cells increases which inhibits immune response
Solution Approach 1:
A LAG-3 blocking agent is introduced as an intermediary substance to interfere with the interaction between LAG-3 and its ligand. This blocking agent prevents LAG-3 from mediating immune inhibition, thereby resolving the contradiction between improved antigen expression and increased immune checkpoint inhibition. The blocking agent acts as a mediator that allows the beneficial antigen expression while counteracting the harmful LAG-3 effect.
Solution Approach 2:
The LAG-3 blocking agent is administered in combination with the MIP DNA vaccine to preemptively counteract the immune inhibitory effect before it can fully suppress the immune response. By applying the blocking agent simultaneously or in a coordinated manner with the vaccine, the harmful LAG-3 mediated inhibition is prevented in advance, allowing the antigen-specific immune response to develop effectively.
2Reliability
If LAG-3 blocking agent is added to MIP DNA vaccine, then immune response efficacy is improved, but treatment complexity increases
Solution Approach 1:
The LAG-3 blocking agent serves multiple functions: it blocks the LAG-3 immune checkpoint pathway to enhance immune response, and when combined with the MIP DNA vaccine, it creates a synergistic effect that improves overall treatment efficacy. This multi-functionality justifies the increased complexity by providing additional therapeutic benefits beyond what the vaccine alone can achieve.
Data Source
AI summary
It is disclosed herein that (a) an anti-tumor DNA vaccine delivered using a MIP DNA vector is a less effective tumor treatment than the corresponding anti-tumor DNA vaccine delivered using a conventional pDNA vector, despite the MIP DNA vector eliciting a higher frequency of antigen-specific CD8+ T cells; and (b) tumor infiltrating CD8+ T cells in animals immunized with the MIP DNA vector express higher levels of the immune checkpoint protein LAG-3 than animals immunized with a conventional pDNA vector, while the expression levels of other immune checkpoint proteins was the same for both groups. Based on these findings, improved methods and compositions for administering DNA vaccines are disclosed. Specifically, DNA vaccines delivered with MIP DNA are administered along with a LAG-3 pathway blocking agent, resulting in a more effective vaccine-induced cellular immune response.