Alphavirus Replicons Reducing Immune Response
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Solution Overview
Problem
The use of alphavirus-based self-amplifying RNAs (replicons) for biotherapeutics is hindered by their self-adjuvanting nature, which can provoke an immune response and induce anti-drug antibodies, reducing the therapeutic effectiveness of the encoded proteins.
Innovation Solution
The development of RNA replicons that encode a heterologous molecule, such as a protein or peptide, along with specific sequences derived from New World and Old World alphavirus nonstructural proteins and hypervariable domains, to diminish or eliminate the immune response against the encoded heterologous molecule.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If alphavirus-based self-amplifying RNAs (replicons) are used for biotherapeutics, then high and prolonged protein expression is achieved, but the self-adjuvanting nature provokes immune response and induces anti-drug antibodies
Solution Approach 1:
The replicon genome is segmented into multiple transcription units, with the immunomodulatory sequence (e.g., PD-1, PD-L1, CTLA-4) separated from the biotherapeutic sequence. This allows independent regulation of immune modulation and therapeutic protein expression, enabling high productivity while controlling harmful immune responses through separate functional modules.
Solution Approach 2:
An immunomodulatory sequence acts as an intermediary between the replicon and the host immune system. This intermediary component (encoding immune checkpoint proteins or cytokines) mediates the interaction by modulating the immune response to the biotherapeutic, thereby reducing anti-drug antibody formation while preserving the self-adjuvanting benefit for sustained expression.
2Reliability
If the replicon is naturally self-adjuvanting and inflammatory, then robust cellular and humoral immunity is driven, but the risk of generating anti-drug antibodies increases
Solution Approach 1:
The immune response parameters are modulated by introducing immunomodulatory sequences that alter the inflammatory profile. By changing the immunological parameters (e.g., adding immune checkpoint inhibition or anti-inflammatory cytokines), the replicon maintains reliable immunity while reducing the harmful anti-drug antibody response through parameter optimization.
Solution Approach 2:
The self-adjuvanting inflammatory nature, which initially causes harmful anti-drug antibodies, is converted into a benefit by strategically deploying immunomodulatory sequences. The inflammation that would normally provoke ADAs is harnessed to enhance therapeutic protein expression, while the immunomodulatory components simultaneously suppress the harmful ADA response, turning the harmful inflammatory response into a controlled beneficial effect.
Data Source
AI summary
The invention provides RNA replicons useful for administering a heterologous protein or peptide into a mammal and eliciting a reduced immune response or no immune response from the mammal. The RNA replicons have RNA sequences encoding for a heterologous protein or peptide, New World alphavirus nonstructural proteins nsP1, nsP2, and nsP4; and an alphavirus nsP3 protein macro domain, central domain, and hypervariable domain. The encoded hypervariable domain can have an amino acid sequence derived from an Old World alphavirus nsP3 hypervariable domain; or can have an amino acid sequence derived from a portion of a New World alphavirus nsP3 hypervariable domain, and another portion derived from an Old World alphavirus nsP3 hypervariable domain.