Single-domain Antibodies Hijack Importin-α for Intracellular Targeting
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Solution Overview
Problem
Current treatments for diseases caused by viral infections and aberrant intracellular components often rely on exogenous targeting sequences or chemical compounds, which can be ineffective, toxic, or non-specific, failing to target only affected cells effectively.
Innovation Solution
Development and use of single-domain antibodies (sdAbs) directed against specific targets like HIV-1 reverse transcriptase, Ebola VP24, and arachidonate 12-lipoxygenase, which can enter cells without additional targeting sequences and selectively target affected cells, administered through various routes for therapeutic, prophylactic, or diagnostic purposes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If exogenous targeting sequences or chemical compounds are used to treat viral infections, then therapeutic agents can be delivered to cells, but the treatments can be ineffective, toxic to unaffected cells, or non-specific
Solution Approach 1:
The sdAbs utilize the cell's own importin-α machinery to enter cells, eliminating the need for exogenous targeting sequences. The sdAbs self-direct to cells expressing importin-α by exploiting the natural cellular import mechanism, achieving specific targeting without external guidance molecules that could cause off-target effects
Solution Approach 2:
The sdAbs act as intermediaries that bridge the therapeutic function and the cell's natural importin-α transport system. By mimicking nuclear localization signals, the sdAbs hijack the importin-α-mediated transport pathway to deliver therapeutic payloads specifically to cells expressing this import machinery
2Adaptability or versatility
If exogenous targeting sequences are added to therapeutic agents, then the agents can cross the cell membrane, but the cell type targeted is limited and manufacturing cost increases
Solution Approach 1:
The sdAbs provide a universal targeting mechanism that works across multiple cell types expressing importin-α, eliminating the need for different targeting sequences for different cell types. A single sdAb design can target various cells including cancer cells, infected cells, or stem cells that express importin-α, greatly enhancing versatility
Solution Approach 2:
The invention extracts and utilizes the naturally occurring importin-α pathway that exists in all eukaryotic cells, rather than adding external targeting sequences. By taking advantage of this endogenous system, the complexity of designing and manufacturing cell-type-specific targeting sequences is eliminated
3Reliability
If conventional antibodies are used to target intracellular components, then high affinity binding can be achieved, but the antibodies cannot access intracellular targets
Solution Approach 1:
The sdAbs serve as intermediaries that exploit the importin-α transport system to gain access to intracellular targets. By incorporating importin-α binding motifs, the sdAbs are transported into the cell cytoplasm and nucleus, enabling them to reach intracellular viral components and aberrant proteins that are inaccessible to conventional antibodies
Solution Approach 2:
The sdAbs represent a segmented approach to antibody design, separating the targeting function from the binding function. The sdAb structure includes an importin-α targeting domain that facilitates cellular entry, while the CDR regions provide high-affinity binding to specific intracellular epitopes, allowing independent optimization of both entry and binding capabilities
Data Source
AI summary
This invention provides compositions and methods to treat a condition or disease without the use of exogenous targeting sequences or chemical compositions. The present invention relates to single-domain antibodies (sdAbs), proteins and polypeptides comprising the sdAbs that are directed against targets that cause a condition or disease. The invention also includes nucleic acids encoding the sdAbs, proteins and polypeptides, and compositions comprising the sdAbs. The invention includes the use of the compositions, sdAbs, and nucleic acids encoding the sdAbs for prophylactic, therapeutic or diagnostic purposes.