Lipid Nanoparticle Composition to Avoid Immune Clearance
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Solution Overview
Problem
Existing lipid nanoparticles (LNPs) induce an innate immune response, leading to accelerated blood clearance (ABC) and dose-limiting toxicity, such as acute phase response (APR) and complement activation-related pseudoallergy (CARPA), due to components like phosphatidylcholine binding to B1 cells and platelets, and PEG-lipids inducing natural IgM and IgG production.
Innovation Solution
Formulations of LNPs that lack phosphatidylcholine and minimize PEG content, incorporating stabilizers like XTEN or PAS peptides, and optionally using anti-platelet agents to inhibit immune responses, thereby reducing recognition and activation by immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If phosphatidylcholine and PEG-lipids are used in LNP formulations, then the LNPs achieve stable structure and delivery function, but they induce innate immune responses leading to accelerated blood clearance and toxicity
Solution Approach 1:
The patent removes phosphatidylcholine from the LNP formulation to eliminate the primary driver of B1 cell activation and CD36-mediated immune responses. It also minimizes or eliminates PEG-lipids to reduce anti-PEG antibody formation and complement activation, thereby extracting the harmful components while retaining the essential LNP structure and delivery function through alternative lipid compositions
Solution Approach 2:
The patent modifies the lipid composition parameters by replacing phosphatidylcholine with alternative lipids such as phosphatidylethanolamine, phosphatidylserine, or neutral lipids. It also adjusts the PEG-lipid content to minimal levels or uses non-PEG stabilizers like polystyrene or polyethylene glycol-free alternatives, changing the chemical parameters to reduce immunogenicity while maintaining LNP integrity
2Reliability
If PEG-lipids are used to cloak the LNP, then the agent is masked from immune recognition, but repeated dosing results in loss of activity due to accelerated clearance
Solution Approach 1:
The patent extracts or minimizes PEG-lipids from the formulation to eliminate the source of anti-PEG antibody formation. Without PEG-lipids or with reduced amounts, the LNP avoids recognition by pre-existing anti-PEG antibodies, preventing accelerated blood clearance upon repeated dosing and maintaining stable half-life and activity over time
Solution Approach 2:
The patent changes the stabilization parameter by replacing PEG-lipids with alternative stabilizing mechanisms such as charge-based stabilization, hydrophobic interactions, or non-immunogenic polymers. This parameter change maintains the cloaking function while eliminating the immunogenicity that causes accelerated clearance on repeat administration
3Productivity
If LNPs are administered to deliver therapeutic agents, then the agents achieve therapeutic effect, but immune interactions cause adverse effects limiting administration frequency and dose
Solution Approach 1:
The patent removes or minimizes immunogenic components (phosphatidylcholine, PEG-lipids) to eliminate the source of adverse immune interactions. This extraction allows the LNP to deliver therapeutic agents effectively while avoiding B1 cell activation, complement activation-related pseudoallergy, and other immune-mediated adverse effects, thereby increasing administration frequency and dose flexibility
Solution Approach 2:
The patent converts the potential harm of immune recognition into a benefit by using alternative lipid compositions that are inherently less immunogenic. The modified LNP formulation maintains delivery efficacy while the reduced immunogenicity transforms a harmful interaction into a beneficial absence of immune activation, enabling safer and more frequent administration
Data Source
AI summary
This disclosure provides improved lipid-based compositions, including lipid nanoparticle compositions, and methods of use thereof for delivering agents in vivo including nucleic acids and proteins. These compositions are not subject to accelerated blood clearance and they have an improved toxicity profile in vivo.