CD47-SIRPα Blockade for Engineered Cell Population Control

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Solution Overview

Problem

Cells engineered to express CD47, such as pluripotent stem cells or T cells, can evade immune rejection and cause uncontrolled growth due to the CD47-SIRPα axis, necessitating a safety mechanism to modulate or eliminate these cells within the patient's immune system.

Innovation Solution

Administering a CD47-SIRPα blockade agent, such as a small molecule, macromolecule, or antibody, to trigger innate immune killing mechanisms, including NK cell and macrophage-mediated killing, to reduce or eliminate the engineered cell population.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If cells are engineered to express CD47 to evade immune rejection, then immune evasion capability is improved, but safety control deteriorates due to uncontrolled growth

Engineering Contradiction:

Improveimmune evasion capabilityVSAvoiduncontrolled growth and tumor formation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies preliminary anti-action by engineering cells with a dual-function CD47 system: endogenous CD47 provides immune evasion, while exogenous inducible CD47 serves as a safety mechanism. The exogenous CD47 is controlled by an inducible promoter that can be activated to trigger immune-mediated cell elimination, preemptively countering the harmful effect of uncontrolled growth before it occurs.

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The patent employs parameter changes by using an inducible promoter system that allows dynamic control of CD47 expression levels. By changing the expression parameter of CD47 from low/endogenous to high/exogenous through induction, the cell population can be switched between immune evasion state and immune recognition state, enabling safety control without permanently compromising therapeutic function.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If CD47 expression is increased to enhance immune evasion, then protection from rejection is improved, but susceptibility to innate immune killing worsens when CD47 is blocked

Engineering Contradiction:

Improveprotection from immune rejectionVSAvoidvulnerability to NK cell and macrophage killing

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies dynamics by creating a dynamic CD47 expression system that can adapt between two states: a protected state with endogenous CD47 expression that provides immune evasion, and a vulnerable state where inducible CD47 expression is activated to trigger immune-mediated elimination. This dynamic control allows the system to transition between protection and elimination as needed, rather than being fixed in one state.

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent implements preliminary action by pre-engineering the cell population with the inducible CD47 safety mechanism in place before transplantation. This preliminary setup ensures that the safety control system is already integrated and functional, ready to be activated if needed, rather than requiring post-transplantation modification or addition of elimination mechanisms.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If safety mechanisms are added to control engineered cells, then cell population control is improved, but system complexity worsens

Engineering Contradiction:

Improvecell population controlVSAvoidgenetic engineering complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies universality by using the CD47 molecule for multiple functions: endogenous CD47 provides natural immune evasion, while exogenous inducible CD47 serves as a safety switch. The same molecular target (CD47) and its receptor (SIRPα) are utilized for both protective and eliminative functions, reducing the need for separate complex systems and leveraging existing biological pathways for dual purposes.

Inventive Principle:

Principle #6Universality (Multi-functionality)

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

Effectively reduces the engineered cell population by 10-100% through immune cell-mediated killing, mitigating adverse events like hyperproliferation and tumor formation.

Implementation Method 1

A CD47-SIRPα blockade agent comprises a small molecule, macromolecule, polypeptide, fusion protein, diabody, antibody, or a combination thereof that binds to CD47 or SIRPα, thus acting on, interfering with, blocking, and/or inhibiting a CD47-SIRPα axis or interaction

Methodology Applied

Scientific EffectCD47-SIRPα axis blocking:

Implementation Method 2

Innate killing mechanisms may be triggered by administration of the CD47-SIRPα blockade agent and can include immune cell-mediated killing of the cells, such as NK-mediated killing, macrophage mediated killing

Methodology Applied

Scientific EffectNK cell-mediated killing:

Implementation Method 3

immune cell-mediated killing of the cells, such as NK-mediated killing, macrophage mediated killing

Methodology Applied

Scientific EffectMacrophage-mediated killing:

Implementation Method 4

ADCC and/or CDC

Methodology Applied

Scientific EffectADCC:

Implementation Method 5

ADCC and/or CDC

Methodology Applied

Scientific EffectCDC:

Data Source

PatentUS20250320290A1METHODS FOR TRIGGERING SAFETY KILLING MECHANISMS USING A CD47-SIRPalpha BLOCKADE AGENT

Publication Date: 2025.10.16 SANA BIOTECHNOLOGY INC

AI summary

The present disclosure provides methods and compositions for administering to a subject in need thereof a CD47-SIRPα blockade agent, wherein the subject was previously administered a population of cells engineered to express an exogenous CD47 polypeptide.