Vectorized Lanadelumab AAV Delivery for Sustained Serum Levels
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Solution Overview
Problem
Current treatments for hereditary angioedema and ocular conditions like diabetic retinopathy and diabetic macular edema require frequent injections of therapeutic antibodies, leading to a significant treatment burden for patients.
Innovation Solution
Gene therapy using recombinant AAV vectors to deliver post-translationally modified therapeutic antibodies, such as lanadelumab, to the liver or muscle, creating a depot for sustained expression and reducing the need for repeated injections by achieving therapeutic serum levels within 20 to 90 days.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic antibodies are administered by repeated injections, then therapeutic serum levels are achieved, but treatment burden increases and peak-trough levels cause variable efficacy
Solution Approach 1:
The patient's own cells (liver or muscle) are engineered to continuously produce the therapeutic antibody through AAV-mediated gene transfer. The transduced cells serve as living factories that autonomously synthesize and secrete the antibody, eliminating the need for external administration and creating a self-sustaining therapeutic system
Solution Approach 2:
The therapeutic antibody production capability is established in advance through a single gene transfer procedure. The AAV vector delivers the transgene to target cells before treatment is needed, creating a permanent or long-lasting capacity for antibody production that provides sustained therapeutic levels without repeated dosing
2Productivity
If gene therapy is used to deliver therapeutic antibodies, then treatment frequency is reduced and consistent levels are achieved, but immunogenicity and safety risks increase
Solution Approach 1:
Adeno-associated virus (AAV) vectors serve as safe intermediaries to deliver the therapeutic transgene into target cells. AAV is chosen because it has low immunogenicity, can establish long-term expression, and has a proven safety profile in clinical applications, thereby mediating between the need for sustained antibody production and the concern about immunogenicity
Solution Approach 2:
The patent optimizes multiple parameters to reduce immunogenicity: selecting AAV serotypes with favorable safety profiles (e.g., AAV8, AAV9), using appropriate promoters to control expression levels, targeting specific tissues (liver or muscle) with favorable immunological characteristics, and engineering the antibody sequence to reduce anti-drug antibody formation while maintaining therapeutic efficacy
3Quantity of substance
If high doses of AAV vectors are administered to achieve therapeutic serum levels, then antibody production is sufficient, but vector-related adverse effects increase
Solution Approach 1:
The patent targets specific tissues (liver or muscle) that have favorable characteristics for antibody production and secretion. By concentrating the gene transfer in these specific locations rather than systemically distributing the vector throughout the body, the approach achieves sufficient antibody levels while limiting vector exposure and potential adverse effects to specific organs with robust safety profiles
Data Source
AI summary
Compositions and methods are described for the delivery of a fully human post-translationally modified therapeutic monoclonal antibody that binds to plasma kallekrein (pKal) to a human subject diagnosed with a disease or condition indicated for treatment with an anti-pKal antibody. Compositions and methods are also described with liver specific promoter combinations to enhance gene expression in liver cells. Such diseases include hereditary angioedema, as well as ocular indications, such as diabetic retinopathy and diabetic macular edema. Dosing of viral vectors encoding the anti-pKal antibody to achieve therapeutically effective serum levels is provided.