Targeted Cbl-b Inhibitor Conjugates for Effector T-Cell Activation
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Solution Overview
Problem
Existing compounds that activate effector T cells for cancer treatment can cause off-target immune reactions, and there is a need for more effective inhibitors of Cbl-b to enhance T cell activation while minimizing these reactions.
Innovation Solution
Development of antibody drug conjugates that specifically target effector T cells by conjugating immune-activating drugs to antibodies recognizing tumor antigens, using Cbl-b inhibitors as payloads, which are attached through various linkers to binding moieties like PD1, to enhance T cell activation and minimize off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If compounds that activate effector T cells are used to treat cancer, then T cell-derived cytokine secretion and proliferation increase, but off-target immune reactions occur
Solution Approach 1:
The patent uses Cbl-b inhibitors as intermediary molecules that specifically modulate T cell activation pathways. By targeting the Cbl-b ubiquitin ligase enzyme, the compound selectively enhances effector T cell function through a defined molecular mechanism while avoiding broad, non-specific immune activation that causes off-target reactions.
Solution Approach 2:
The invention changes the molecular parameters of T cell activation by inhibiting Cbl-b, a specific negative regulator. This targeted parameter change (blocking Cbl-b-mediated ubiquitination) selectively enhances T cell cytokine secretion and proliferation without triggering the uncontrolled immune responses that characterize off-target reactions.
2Reliability
If conventional Cbl-b inhibitors are developed, then T cell activation is enhanced, but selectivity and reduced off-target effects are needed
Solution Approach 1:
The patent applies local quality by designing a Cbl-b inhibitor with specific molecular characteristics ( Formula I structure with particular substituents) that confer selective binding to Cbl-b. This localized molecular design ensures the compound acts specifically on the intended target (Cbl-b enzyme in T cells) while maintaining high reliability of T cell activation and minimizing effects on other immune cells or pathways.
Data Source
AI summary
The present disclosure provides antibody drug conjugates and methods of delivering the conjugates to effector T cells. Also disclosed are novel Cbl-b inhibitors. The compounds and conjugates are useful for treating diseases in subjects in need thereof.