Serina Therapeutics (SER) Investor presentation summary

Immunogenicity and adverse reactions to PEGylated LNPs

• High incidence of anaphylaxis observed with mRNA vaccines, not classically IgE-mediated but linked to anti-PEG IgM and IgG antibodies that activate complement and alter LNP integrity.

• Basophil activation and complement cascade, particularly C5a, are implicated in vaccine-induced hypersensitivity, with IgG and IgM to PEG as primary mediators.

• Anti-PEG antibodies are boosted significantly post-vaccination, especially with Moderna's formulation, and are present in most individuals even before vaccination.

• These antibodies bind to immune cells, leading to increased association of nanoparticles with granulocytes and monocytes, and can compromise nanoparticle efficacy.

• Adverse events and loss of efficacy have been documented in PEGylated therapies, such as PEGrFVIII and ONPATTRO, correlating with anti-PEG antibody titers.

Limitations of PEG-lipid LNPs and the PEOZ-lipid alternative

• PEG-lipid LNPs induce robust IgM and IgG responses in both humans and animal models, leading to potential hypersensitivity and reduced therapeutic efficacy.

• Pre-existing anti-PEG antibodies are linked to immediate allergic reactions and loss of efficacy in PEGylated drugs, as seen in clinical trials and real-world cases.

• PEOZ-lipid LNPs, developed as an alternative, show nearly identical biophysical properties to PEG-lipid LNPs but do not elicit detectable IgM or IgG responses upon repeat dosing.

• PEOZ-lipid LNPs selectively target antigen-presenting cells in vivo, a novel and reproducible observation across different LNP formulations.

• The use of PEOZ-lipid may provide a safer and more effective platform for programmable drug delivery, avoiding the immunogenicity issues of PEG-lipids.

Clinical and translational implications

• The widespread use of PEG-lipids in mRNA vaccines and therapeutics has led to increased awareness of anti-PEG antibody-mediated adverse events.

• Alternatives like PEOZ-lipid could mitigate risks of anaphylaxis and loss of efficacy, supporting safer repeat dosing and broader application in drug delivery.

• The findings support a shift in LNP formulation strategies for future vaccine and therapeutic development.