Antibody-CD4 Conjugates for HIV Neutralization and Infected Cell Elimination
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Solution Overview
Problem
Current antiretroviral therapies for HIV infection are unable to fully restore health or a normal immune status and are plagued by co-morbidities, with a need for improved therapeutics that can effectively target and eliminate HIV-infected cells.
Innovation Solution
Development of antibody conjugates comprising an anti-CoRBS or anti-Cluster A antibody linked to a CD4 molecule or CD4 mimetic compound, forming Ab-CD4 or Ab-CD4mc conjugates that can neutralize HIV virions and mediate Fc-effector activities, including ADCC and ADCP, to target and eliminate HIV-infected cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current antiretroviral therapies are used, then HIV replication can be controlled, but they are unable to fully restore health or a normal immune status and are plagued by co-morbidities
Solution Approach 1:
The patent combines anti-Env antibodies with CD4 molecules or CD4 mimetic compounds to create conjugate structures that simultaneously achieve HIV replication control and eliminate HIV-infected cells through Fc-mediated effector functions, thereby addressing both viral control and immune restoration without the co-morbidities associated with long-term antiretroviral therapy
Solution Approach 2:
The antibody conjugates perform multiple functions: they neutralize free HIV virions through antibody binding, eliminate HIV-infected cells through Fc-mediated ADCC and ADCP, and restore immune function by engaging immune effector cells, thereby providing a comprehensive therapeutic solution that goes beyond simple viral replication control
2Adaptability or versatility
If non-neutralizing antibodies target occluded Env epitopes, then they lack direct neutralization activity, but they can mediate Fc-effector activities against infected cells
Solution Approach 1:
The patent merges non-neutralizing antibodies that target occluded Env epitopes with CD4 molecules or CD4 mimetic compounds in conjugate structures. This combination allows the antibodies to maintain their epitope-binding capability while the CD4 component provides direct neutralization activity by blocking the CD4 binding site on Env, thereby achieving both versatile epitope targeting and reliable direct neutralization
Solution Approach 2:
The CD4 molecule or CD4 mimetic compound acts as an intermediary that bridges the non-neutralizing antibody and the Env trimer. It binds to the CD4 binding site on Env, inducing conformational changes that expose occluded epitopes for antibody binding, while simultaneously providing direct neutralization activity and enabling Fc-effector functions
Data Source
AI summary
The present disclosure provides for antibody conjugate molecules (Ab-CD4 conjugates) comprising an antibody, at least one linker, and at least one CD4 compound, wherein the at least one linker links the antibody to the at least one CD4 compound and wherein the Ab-CD4 conjugate is capable of neutralizing an HIV virus, as well as methods of killing HIV-infected cells through an Fc-mediated effector function using the Ab-CD4 conjugates. Also provided are pharmaceutical compositions comprising the Ab-CD4 conjugates and methods of treating or preventing HIV injection in a subject.