Trispecific Binding Proteins for T-Cell Bridging and 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, such as 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 anti-retroviral therapy (ART) is used to treat HIV/AIDS, then viral replication is inhibited and viremia is reduced to undetectable levels, but latent HIV-1 reservoirs in CD4+ T cells are not eliminated and recur upon treatment cessation
Solution Approach 1:
The patent uses bispecific T cell engaging antibodies as intermediaries to bridge CD3+ T cells and HIV reservoir cells. These antibodies have dual specificity: one arm binds to CD3 on T cells while the other arm binds to HIV reservoir cells, enabling T cell activation and killing of reservoir cells without directly targeting the latent virus itself
Solution Approach 2:
The bispecific T cell engaging antibodies perform multiple functions simultaneously: they activate T cells, facilitate T cell proliferation, enable target recognition, and mediate cytotoxic killing of HIV reservoir cells. This multi-functionality addresses both viremia control and reservoir elimination in a single therapeutic agent
2Reliability
If existing immunotherapies are used to activate T cells, then some immune response is achieved, but T cell activation and tumor cell elimination are insufficient
Solution Approach 1:
The bispecific antibodies serve as intermediaries that physically bridge activating T cells with tumor target cells. The antibody structure includes one binding domain for CD3 on T cells and another binding domain for tumor-associated antigens, creating a stable immunological synapse that enhances T cell activation and tumor cell killing efficiency
Solution Approach 2:
The bispecific T cell engaging antibodies are composite molecular structures combining specificity for two different targets (CD3 and tumor antigens) in a single antibody molecule. This composite structure enables simultaneous engagement of T cells and tumor cells, producing synergistic immune activation and tumor elimination effects
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.