Recombinant Particle Compositions for Targeted In Vivo CAR Delivery
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Solution Overview
Problem
In vivo gene therapies face challenges in delivering therapeutic payloads efficiently to specific cell types, such as BCMA-expressing cells, due to inefficient on-target delivery and substantial off-target delivery, which has hindered their potential in treating diseases like multiple myeloma.
Innovation Solution
Recombinant lentiviral particles engineered with a mutated vesiculovirus envelope glycoprotein and a tropism polypeptide that binds immune effector cells, combined with a lentiviral vector encoding a chimeric antigen receptor for BCMA, enhance targeted delivery and transduction of immune cells in vivo.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional lentiviral vectors are used for in vivo gene therapy delivery, then broad cell tropism is achieved, but off-target delivery to non-target cells occurs and on-target delivery efficiency is reduced
Solution Approach 1:
The viral envelope is segmented into two functional components: a mutated vesiculovirus glycoprotein that provides cell fusion capability and a specialized targeting moiety that provides specific binding to immune effector cells. This segmentation allows independent optimization of fusion and targeting functions, achieving high targeting accuracy without excessive complexity.
Solution Approach 2:
The delivery system uses a composite envelope structure combining mutated vesiculovirus glycoprotein with specialized targeting moieties (such as anti-CD19 scFv or other immune cell-specific ligands). This composite approach integrates both fusion and targeting functionalities into a single envelope structure, resolving the contradiction between reliability and complexity.
2Productivity
If specialized targeting moieties are used to improve on-target delivery, then delivery efficiency to specific cell types increases, but off-target delivery to undesired cell types is not sufficiently abrogated
Solution Approach 1:
The targeting moiety is localized specifically to the viral envelope surface with high density and specificity for immune effector cells. This local concentration of targeting function ensures that the vector preferentially binds to and delivers cargo to the intended target cells, minimizing off-target effects while maximizing delivery efficiency.
Solution Approach 2:
The vesiculovirus glycoprotein is mutated to alter its properties: it loses the ability to bind its native receptor (reducing off-target effects) while retaining or enhancing cell fusion capability. This parameter change in the glycoprotein's binding specificity, combined with the added targeting moiety, resolves the contradiction between productivity and harmful factors.
3Manufacturing precision
If ex vivo gene therapy approaches are used, then controlled manufacturing environment is achieved, but complex cell harvesting and reinfusion procedures are required
Solution Approach 1:
The engineered lentiviral particles are designed for in vivo self-administration to immune effector cells circulating in the patient's bloodstream. The particles autonomously navigate to and enter target cells without requiring external cell harvesting, manipulation, or reinfusion procedures. This self-service approach maintains manufacturing precision while dramatically simplifying the treatment procedure.
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
The engineered particles achieve efficient and specific delivery of the chimeric antigen receptor to BCMA-expressing cells, potentially offering a durable and curative treatment for multiple myeloma by enhancing the efficacy and safety of in vivo CAR T cell therapy.
Implementation Method 1
a mutated vesiculovirus envelope glycoprotein
Implementation Method 2
a tropism polypeptide that binds to an immune effector cell
Data Source
AI summary
The present disclosure provides compositions and methods comprising recombinant particles suitable for specifically delivering one or more chimeric antigen receptors to immune effector cells in vivo.