Modular Glycopolymer Technology for Antigen-Specific Immune Tolerance
SUMMARY
This technology achieves significant reduction of anti-drug antibody responses through synthetically mannosylated antigen conjugation that induces antigen-specific humoral tolerance by enhancing hepatic immune tolerance mechanisms.
The Unmet Need: Effective mitigation of immunogenicity in biologic therapeutics to prevent anti-drug antibody formation
- Biologic drugs frequently trigger immune responses leading to anti-drug antibody (ADA) formation, which compromises both safety and efficacy, thus limiting therapeutic utility; current methods to prevent ADA are inadequate and lack antigen specificity. This immune response contributes to treatment failure in multiple clinical indications, and existing approaches do not consistently induce durable tolerance to biologics.
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There is a growing industry trend towards employing targeted immunomodulation to overcome immunogenicity challenges, leveraging the organ-specific immune environment, particularly the liver's capacity to induce immune tolerance, to improve clinical outcomes for patients receiving biologic therapies.
The Proposed Solution: Modular synthetic mannose polymer conjugation to biologics enhances liver-mediated antigen-specific immune tolerance
- The faculty inventor developed a synthetic mannose polymer, p(Man), that can be covalently linked to a wide range of protein biologics to facilitate targeted delivery to the liver, a site conducive to immune tolerance induction; this approach promotes antigen-specific T cell tolerance and substantially reduces ADA formation compared to unconjugated proteins. Unlike prior nonspecific immunosuppressive strategies, this method enhances antigen presentation within hepatic tolerance pathways and downregulates T follicular helper and B cell responses as validated in murine models with highly immunogenic proteins such as recombinant uricase and E. coli asparaginase. Transcriptomic profiling supports the mechanism involving increased T cell receptor signaling, apoptosis, and exhaustion, collectively impairing ADA responses. While current validation is preclinical, the platform shows promise for broad applicability across biologics and potential long-term modulation of immunogenicity.
ADVANTAGES
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Antigen-specific humoral tolerance induction
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Targeted delivery to immunotolerant liver environment
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Modular conjugation compatible with various biologics
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Reduced anti-drug antibody formation
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Mechanism supported by transcriptomic evidence
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Preclinical validation in highly immunogenic protein models
APPLICATIONS
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Mitigation of immunogenicity in biologic therapeutics (e.g., recombinant uricase, asparaginase)
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Treatment of antibody-mediated diseases requiring biologic drug efficacy
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Prevention of anti-drug antibody formation in chronic biologic administration