Antibody Cytoplasmic Delivery via Anionic Polypeptide and Cationic Agent
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Solution Overview
Problem
Current methods for delivering antibodies into cells are inefficient, with most small molecule drugs facing challenges in reaching intracellular targets due to lack of natural ligands, poor pharmacokinetic properties, and off-target toxicity, and existing protein transfection systems struggle with low efficacy and reproducibility, especially in delivering antibodies cytoplasmically.
Innovation Solution
Compositions comprising an antibody or protein, an anionic polypeptide or nucleic acid, and a cationic transfection agent, where the anionic component and cationic agent facilitate cytoplasmic delivery, using a modular approach that includes chemical conjugation and site-specific attachment of anionic polypeptides to antibodies, enabling efficient encapsulation and cytoplasmic release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If cell-penetrating peptide (CPP) based methods are used for cytoplasmic antibody delivery, then cellular uptake is induced, but endosome escape efficiency is vanishingly small
Solution Approach 1:
The delivery system is divided into separate functional components: the CPP handles cellular uptake while the cargo (antibody) is delivered separately to the cytoplasm, avoiding the bottleneck of endosome escape that plagues conventional CPP-cargo conjugates
Solution Approach 2:
The patent uses an intermediary mechanism (electroporation or microinjection) to bypass the endosome entirely and deliver the cargo directly to the cytoplasm, eliminating the need for endosome escape while maintaining CPP-mediated cellular uptake
2Ease of manufacture
If protein transfection systems are used, then encapsulation into nanoparticles is achieved, but delivery efficacy and reproducibility are poor
Solution Approach 1:
The patent performs preliminary conjugation of the cargo to a delivery moiety outside the cell, ensuring proper orientation and stability before introduction, which improves both efficacy and reproducibility compared to random encapsulation
Solution Approach 2:
The patent optimizes key parameters including the length and composition of the CPP, the ratio of CPP to cargo, and the electroporation conditions to achieve consistent high-efficiency delivery across different cell types and cargo
3Adaptability or versatility
If small molecule drugs are used to target intracellular proteins, then ligand binding is required, but many targets lack natural ligands or binding sites
Solution Approach 1:
The patent uses antibodies that naturally bind to protein epitopes as templates to create intracellular therapeutics, copying the high specificity and affinity of natural antibody-antigen interactions to achieve precise target engagement without off-target effects
Solution Approach 2:
The patent creates a composite delivery system combining the high specificity of antibodies with the cell-penetrating capability of CPPs, enabling intracellular delivery of highly specific therapeutics that would otherwise be unable to enter cells
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Achieves high transfection efficiency of antibodies into cells with minimal cytotoxicity, exceeding 60% delivery at sub-micromolar concentrations, and preserves the binding affinity of the antibodies, addressing the limitations of existing delivery methods.
Implementation Method 1
cargo proteins are encapsulated into lipid or polymer nanoparticles that can induce endocytic uptake and then destabilize the endosome membrane to allow for cytoplasmic release of cargo proteins
Implementation Method 2
compositions having an anionic polypeptide and a cationic transfection agent
Data Source
AI summary
The invention provides compositions and methods for the cytoplasmic delivery of antibodies and other proteins. Specifically, provided herein are compositions having an anionic polypeptide and a cationic transfection agent for facilitating the cytoplasmic delivery of an antibody or a protein.