Bispecific Antigen-Binding Polypeptides for Lysosomal Viral Clearance
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Solution Overview
Problem
Current methods for removing unwanted agents such as viruses and toxins from the body, like antiretroviral therapy and broad neutralizing antibodies, are inadequate due to immune evasion by pathogens and high mutation rates, necessitating lifelong treatment and lacking efficient clearance mechanisms.
Innovation Solution
Development of bispecific antigen-binding polypeptides that bind to both extracellular molecules and cell surface proteins, facilitating internalization and degradation of these agents via the lysosomal pathway, independent of a functional immune system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antiretroviral therapy is used to suppress viral replication, then viral load is reduced and AIDS-related morbidity is reduced, but HIV persists in latent reservoirs and requires lifelong treatment
Solution Approach 1:
The patent applies preliminary action by using broadly neutralizing antibodies to preemptively neutralize and clear HIV from circulation before latent reservoirs can reseed active infection. The bNAbs are administered to proactively eliminate free virus particles, preventing them from infecting new cells and establishing new reservoirs, thereby potentially allowing treatment interruption.
Solution Approach 2:
The patent changes the parameter of viral clearance mechanism by transitioning from antiretroviral drugs that suppress replication to broadly neutralizing antibodies that directly neutralize and facilitate clearance of virus particles through immune mechanisms, fundamentally altering how HIV is removed from the body.
2Reliability
If broadly neutralizing antibodies are used to inhibit viral entry, then viral replication is suppressed, but antibody-resistant viral variants emerge due to high mutation rate
Solution Approach 1:
The patent applies universality by using broadly neutralizing antibodies that target multiple conserved epitopes on the HIV envelope glycoprotein, enabling a single antibody or combination to neutralize diverse HIV strains. This multi-epitope approach reduces the likelihood of resistance development compared to single-epitope antibodies.
Solution Approach 2:
The patent employs composite strategies by combining multiple broadly neutralizing antibodies with different epitope specificities, creating a multi-layered neutralization barrier. This composite approach ensures that mutations conferring resistance to one antibody do not necessarily confer resistance to others, thereby preventing viral escape.
3Reliability
If conventional antibodies are used to bind viruses in circulation, then viral entry is blocked, but actual clearing rate of HIV is compromised and viruses remain in circulation
Solution Approach 1:
The patent uses Fc domain-containing antibody structures as intermediaries that not only neutralize HIV but also engage with Fc receptors on immune cells. This intermediary mechanism facilitates the transfer of neutralized virus particles to immune cells for degradation, actively accelerating clearance rather than passive circulation.
Solution Approach 2:
The patent enables self-service by designing antibodies with Fc domains that automatically engage with the immune system's clearance mechanisms. The antibody-virus complexes self-propagate to immune cells expressing Fc receptors, which then internalize and degrade the complexes, creating a self-amplifying clearance system without requiring external intervention.
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
Efficient clearance of pathogens like HIV and toxins by targeting them to ubiquitously expressed receptors like EGFR for internalization and degradation, providing a rapid and broad-spectrum solution.
Implementation Method 1
a second antigen-binding domain that binds to a cell surface protein, whereby the cell surface protein mediates internalisation of the bound complex
Implementation Method 2
the extracellular molecule is internalised and degraded via the lysosomal pathway
Data Source
AI summary
The present invention relates to bispecific antigen-binding polypeptides that may be used to remove unwanted agents, such as viruses or toxins, from the body and target them for degradation. The bispecific antigen-binding polypeptides of the invention have a first antigen-binding domain that binds an extracellular molecule and a second antigen-binding domain that binds to a cell surface protein, whereby the cell surface protein mediates internalisation of the bound complex. The invention also relates to pharmaceutical compositions comprising the bispecific antigen-binding poly peptides, and to methods of targeting an extracellular molecule for cellular internalisation and degradation via the lysosomal pathway.