Multimeric Polypeptide Activation of HIV-Specific CTLs

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Solution Overview

Problem

Current biologic and cell-based therapies for HIV infection face challenges such as severe side effects, logistical issues with scalability and toxicity, and limited ability to rapidly identify and amplify HIV-specific cytotoxic T lymphocyte function, hindering the development of effective cures or lifelong remission strategies.

Innovation Solution

A multimeric polypeptide comprising an HIV epitope, major histocompatibility complex (MHC) peptides, and costimulatory domains or cytokines is used to selectively modulate the activity of HIV-specific T cells, enhancing their cytotoxic capacity and ability to eliminate latent HIV-infected cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If immunomodulatory biologics are used to stimulate anti-HIV immune responses, then HIV-specific CTL function is enhanced, but serious side effects and fatalities occur due to untargeted global immune stimulation

Engineering Contradiction:

ImproveHIV-specific CTL functionVSAvoidside effects and fatalities

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing HLA-mismatched multimeric polypeptides that specifically target and activate only HIV-specific CD8+ T cells with the correct TCR specificity, rather than providing non-specific global immune stimulation. The costimulatory domains are localized to the polypeptide structure, ensuring targeted activation of only the desired cell population.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses HLA-mismatched multimeric polypeptides as intermediary molecules that bridge the gap between the HIV epitope and T cell activation. These polypeptides serve as a mediator to specifically stimulate HIV-specific CTLs without causing widespread immune activation, thereby avoiding the harmful side effects of traditional immunomodulatory biologics.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If cell-based therapies with CAR-T cells are used to eliminate HIV-infected cells, then HIV-specific cytotoxic activity is improved, but logistical challenges and toxicities arise from ex vivo transduction and expansion

Engineering Contradiction:

ImproveHIV-specific cytotoxic activityVSAvoidlogistical challenges and toxicities

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent extracts the essential function of CAR-T cell therapy (specific targeting of HIV-infected cells) while removing the complex ex vivo transduction and expansion steps. The HLA-mismatched multimeric polypeptides provide the targeting capability in a simplified in vivo approach, eliminating the need for complex cell manipulation procedures.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent employs disposable, non-replicating multimeric polypeptide molecules that perform their function and are then cleared from the system. This eliminates the need for long-term maintenance of genetically modified cells, reducing logistical complexity and potential toxicities associated with persistent cell-based therapies.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Quantity of substance

If latency reversing agents are used to reactivate latent HIV-infected cells, then the latent reservoir becomes visible to the immune system, but the intrinsic anti-HIV immune response fails to effectively eliminate the reactivated cells

Engineering Contradiction:

Improvevisibility of latent reservoirVSAvoidelimination of reactivated cells

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies preliminary action by pre-activating and expanding HIV-specific CD8+ T cells in vitro using HLA-mismatched multimeric polypeptides before administration to the patient. This ensures that the immune response is already primed and enhanced capacity to eliminate reactivated latent cells is prepared in advance.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent changes the parameter of T cell activation by introducing costimulatory domains that alter the activation threshold and functional capacity of HIV-specific CD8+ T cells. This enhances their ability to effectively kill reactivated latent cells, overcoming the limitation of the intrinsic immune response.

Inventive Principle:

Principle #35Parameter changes

4Reliability

If ex vivo antigen-specific stimulation is used to restore in vitro CTL capacity, then killing capacity is improved, but the approach lacks in vivo activity and scalability

Engineering Contradiction:

Improvein vitro killing capacityVSAvoidin vivo activity and scalability

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent replaces the mechanical in vitro culture system with an in vivo administration approach. The HLA-mismatched multimeric polypeptides are administered directly to the patient, eliminating the need for complex ex vivo cell culture and stimulation procedures while maintaining and enhancing CTL function in the living organism.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS11407806B2Precision activation of HIV-specific CTLS to eliminate reactivated latent T cells

Publication Date: 2022.08.09 ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV

AI summary

Compositions and methods to increase the in vivo capacity of CD8+ T cells to kill HIV-infected and reactivated latent HIV-infected T cells (LHITC) to functionally cure HIV infection or improve the clinical course. Compositions and methods to increase the in vivo capacity of CD8+ T cells to kill CMV or CMV-infected cells are also provided.