Trispecific Binding Proteins for T-Cell Activation and HIV Reservoir Killing
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Solution Overview
Problem
Current treatments for HIV/AIDS, such as anti-retroviral therapy (ART), fail to eliminate the latent HIV-1 reservoirs in CD4+ T cells, leading to recurring viremia upon treatment cessation, and existing immunotherapies are limited in activating and eliminating tumor cells effectively.
Innovation Solution
Development of trispecific binding proteins, like anti-CD28/CD3 and anti-CD38/CD3 antibodies, that recruit and activate T cells to target HIV reservoirs and tumor cells, providing dual signaling for enhanced immune response and cell killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ART drugs are used to target internal HIV-1 proteins, then HIV-1 replication is inhibited and viremia is reduced to undetectable levels, but the latent HIV-1 reservoirs in CD4+ T cells are not eliminated and recurring viremia occurs upon treatment cessation
Solution Approach 1:
The patent uses bispecific antibodies as intermediaries that bridge T cells and HIV reservoirs. These antibodies have dual specificity: one arm binds to HIV antigens on reservoir cells while the other arm binds to T cell receptors or co-receptors, thereby mediating the interaction and enabling T cell-mediated elimination of reservoirs without directly targeting internal viral proteins
Solution Approach 2:
The bispecific antibodies perform multiple functions simultaneously: they target HIV reservoirs, activate T cells, and facilitate immune synapse formation. This multi-functionality allows a single therapeutic agent to address both the suppression of active replication and the elimination of latent reservoirs
2Reliability
If monoclonal antibodies are engineered to be bisspecific for targeting both tumor cells and T cells, then T cell activation and tumor cell killing are enhanced, but the structural complexity of the antibody increases
Solution Approach 1:
The bispecific antibody is constructed by segmenting two different monoclonal antibody specificities into a single molecule. Each antibody arm retains its original specificity (one for tumor antigen, one for T cell target) while being connected through engineered hinge regions, allowing independent folding and binding of each domain
Solution Approach 2:
The patent merges two separate monoclonal antibody functions into a single bispecific antibody molecule. The heavy chains and light chains are engineered to pair in a cross configuration, where one heavy chain pairs with one light chain to form one antigen-binding site, and the other heavy chain pairs with the other light chain to form the second antigen-binding site
3Reliability
If T cells are recruited to tumor cells through antibody mediation, then tumor cell killing is enhanced, but the ability to eliminate latent HIV reservoirs is limited
Solution Approach 1:
The patent designs antibodies with universal applicability to multiple pathogen systems. By targeting conserved T cell co-receptors (such as CD28, CD40) rather than pathogen-specific markers, the same antibody platform can be adapted to target both HIV reservoirs and tumor cells, enabling dual functionality across different disease contexts
Data Source
AI summary
Provided herein are trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation, and wherein and a second pair of polypeptides possess a single variable domain forming a single antigen binding site. In some embodiments, the binding proteins comprise a binding site that binds a CD28 polypeptide, a binding site that binds a CD3 polypeptide, and a binding site that binds a third polypeptide, such as a tumor target protein. In some embodiments, the binding proteins comprise four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins. The disclosure also relates to methods for making trispecific and/or trivalent binding proteins and uses of such binding proteins.