Dual-Binding Macromolecule Targeting to Minimize Off-Target Effects

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Solution Overview

Problem

Existing therapeutic agents often cause undesirable off-target effects due to the presence of desirable targets in both healthy and diseased tissues, leading to inefficiencies and potential harm.

Innovation Solution

The development of macromolecules, such as ANDbodies, which incorporate an effector target binding domain and an address target binding domain, allowing for targeted delivery to specific cells, tissues, or organs while minimizing off-target effects by using a second binding site that localizes the first site without influencing signaling and is connected to a small molecule via a linker.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If therapeutic agents are delivered systemically to reach effector targets in diseased tissues, then the therapeutic effect is achieved, but off-target effects occur in healthy tissues where the same effector targets are also present

Engineering Contradiction:

Improvetherapeutic effectVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The targeting system is segmented into two independent domains: an address target binding domain for localization and an effector target binding domain for therapeutic action. This segmentation allows the effector domain to remain inactive during systemic circulation and only become functional when localized to the target tissue via the address domain, thereby achieving therapeutic effect while minimizing off-target effects.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The address target binding domain serves as an intermediary that mediates between the systemic circulation and the effector target. It localizes the macromolecule to the target tissue first, and only then does the effector target binding domain engage its target, preventing premature or off-target activation of the therapeutic agent.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Power

If the effector target binding domain is made highly potent to enhance therapeutic effect, then signaling efficacy is improved, but off-target binding and harmful effects increase

Engineering Contradiction:

Improvesignaling efficacyVSAvoidoff-target binding

Core Design Contradiction:

PowerVSObject-affected harmful factors

Solution Approach 1:

The address target binding domain performs the preliminary action of localization to the target tissue before the effector target binding domain engages its target. This preliminary localization ensures that even high-potency effector domains only exert their full signaling efficacy at the correct location, preventing off-target binding while maintaining therapeutic power.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The macromolecule exhibits different binding characteristics in different locations: in systemic circulation, the effector domain has low effective affinity due to lack of localization; at the target tissue, the effector domain achieves high local concentration and potent binding. This spatial variation in binding quality allows high potency where needed while minimizing off-target effects.

Inventive Principle:

Principle #3Local quality

3Manufacturing precision

If the macromolecule is designed with two binding domains for targeted delivery, then specificity is improved, but the molecular complexity increases

Engineering Contradiction:

Improvetargeting specificityVSAvoidmacromolecule structure

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

Two separate functional domains (address target binding domain and effector target binding domain) are merged into a single macromolecular structure. This combining approach achieves the dual functionality of targeted localization and therapeutic action while simplifying the overall system compared to using separate molecules or complex delivery mechanisms.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The macromolecule is designed with multi-functionality, where a single molecule performs both localization (via address domain) and therapeutic action (via effector domain). This universal design reduces the number of separate components needed while maintaining high targeting specificity and therapeutic efficacy.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20250353906A1Compositions and methods for targeted delivery of therapeutic agents

Publication Date: 2025.11.20 FLAGSHIP PIONEERING INNOVATIONS VII LLC

AI summary

Macromolecule compositions and related methods that effect targeted delivery of therapeutic agents to effector targets in a desired cell, tissue and/or organ of interest while minimizing or avoiding undesirable delivery to other cells, tissues or organs are provided. Compositions and methods related to macromolecules, such as an ANDbody™, that include an effector target binding domain specific for an effector target, and an address binding domain specific for an address target are described. The macromolecules are linked to small molecules.