TEAC and ATTAC Immunooncology Agents for Targeted T-Cell Activation
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Solution Overview
Problem
Current immunotherapeutic strategies for cancer treatment, such as bispecific T-cell Engaging Antibodies (BiTEs), lack specificity to tumor cells and can cause cytokine release syndrome due to non-specific activation of T cells, necessitating a solution to limit T-cell activation and improve therapeutic index.
Innovation Solution
Development of Targeted T-cell Engaging Agents (TEACs) and Antibody Tumor-Targeting Assembly Complexes (ATTACs) with half-life extension moieties, comprising targeting moieties, T-cell engaging domains, inert binding partners, and protease cleavage sites, allowing for targeted and controlled T-cell activation within the tumor microenvironment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bisspecific T-cell Engaging Antibodies (BiTEs) are used to activate T cells, then T-cell activation is achieved, but non-specific activation occurs leading to cytokine release syndrome
Solution Approach 1:
The antibody is divided into two separate components: a first component with a first T-cell engaging domain and a second component with a second T-cell engaging domain. These components are kept separate during administration and only become functional when they associate with target cells through their targeting moieties, thereby activating T cells specifically at the tumor site rather than systemically.
Solution Approach 2:
The antibody components are designed with targeting moieties that confer specificity to tumor cells. The first and second components each bind to different tumor antigens, ensuring that T-cell activation occurs locally at the tumor site rather than systemically throughout the body, thus preventing cytokine release syndrome.
2Reliability
If current bispecific antibodies are used, then T-cell engagement is achieved, but specificity to tumor environment is insufficient
Solution Approach 1:
The bispecific antibody is segmented into two separate components, each with its own targeting moiety specific to different tumor antigens. This segmentation allows each component to independently bind to its specific tumor antigen, enhancing the overall specificity to the tumor environment while maintaining T-cell engagement capability.
Solution Approach 2:
Each antibody component is equipped with a targeting moiety that provides local specificity to particular tumor antigens. The first component targets a first tumor antigen and the second component targets a second tumor antigen, ensuring that T-cell engagement occurs specifically within the tumor microenvironment rather than elsewhere in the body.
3Loss of time
If half-life extension moiety is added to TEAC or ATTAC, then dosing frequency is reduced, but agent complexity increases
Solution Approach 1:
The half-life extension moiety is merged with one of the antibody components (either the first or second component). This combining approach extends the circulating half-life of the antibody complex, reducing dosing frequency, while integrating the extension function into the existing agent structure rather than adding a completely separate system.
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
These agents enable targeted and controlled T-cell activation, reducing off-target effects and cytokine release, potentially improving treatment efficacy and safety by extending half-life and reducing dosing frequency, thereby enhancing specificity and therapeutic index.
Implementation Method 1
a protease cleavage site separating the first T-cell engaging domain and the first inert binding partner, wherein the protease cleavage site is capable of releasing the inert binding partner and half-life extending moiety from the T-cell engaging domain in the presence of a protease
Implementation Method 2
These TEACs and ATTACs may have, for example, longer half-life or comprise multiple components in a single agent
Data Source
AI summary
The present disclosure provides targeted T-cell engaging agents (TEAC) and antibody tumor-targeting assembly complexes (ATTAC) for targeting to cancer. The TEAC or ATTAC described herein may have, for example, longer half-life or comprise multiple components in a single agent.