Engineered Tether Proteins for Apoptotic Cell Immunogenicity

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

The clearance of apoptotic cells by macrophages can limit the immunogenicity of tumor cells, making it difficult to mount an effective immune response against cancer, as the homeostatic clearance mechanisms suppress inflammatory turnover and immune activation.

Innovation Solution

Engineered tether proteins that link apoptotic cells to immunogenic receptors, blocking homeostatic elimination and activating immune pathways by combining a phosphatidylserine binding domain with an immunostimulatory domain, such as the Fc region of human IgG1, to enhance the recognition and processing of apoptotic cells by immune cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If macrophages clear apoptotic cells through homeostatic mechanisms, then tissue homeostasis is maintained and inflammation is prevented, but immunogenicity of tumor cells is suppressed and immune response against cancer is limited

Engineering Contradiction:

Improvetissue homeostasisVSAvoidsuppression of immune response

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses engineered tether proteins as intermediaries that bridge apoptotic cells and immunogenic receptors. These tether proteins contain a phosphatidylserine binding domain that binds to apoptotic cells and an immunostimulatory domain that activates immune pathways, thereby mediating the transition from homeostatic clearance to immunogenic activation without disrupting either function

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention alters the clearance parameters of apoptotic cells by changing the recognition signals. By modifying the surface properties of apoptotic cells through tether protein attachment, the cells are redirected from homeostatic clearance pathways to immunogenic pathways, changing the fate parameter from disposal to immune activation

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If apoptotic cells are rapidly engulfed by macrophages, then chronic inflammation is prevented and autoimmune response is avoided, but inflammatory turnover and immune activation are suppressed

Engineering Contradiction:

Improveprevention of chronic inflammationVSAvoidimmune activation

Core Design Contradiction:

Object-affected harmful factorsVSProductivity

Solution Approach 1:

The patent applies preliminary action by pre-coating apoptotic cells with tether proteins before macrophage encounter. This preliminary modification ensures that when macrophages encounter the apoptotic cells, the immunogenic signals are already in place to activate immune pathways, preventing the default homeostatic clearance outcome

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention inverts the normal clearance paradigm by preventing macrophage engulfment through tether protein attachment. Instead of allowing rapid engulfment that suppresses immunity, the tether proteins block macrophage interaction and redirect the apoptotic cells to alternative immunogenic pathways, effectively inverting the clearance outcome

Inventive Principle:

Principle #13The other way round (Inversion)

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

This approach promotes inflammatory turnover and immunogenicity of apoptotic cells, enhancing the immune response against cancer cells and improving the efficacy of cancer therapies by increasing the activation of immune cells within the tumor microenvironment.

Implementation Method 1

PS and PS-OX, as well as other phospholipids such as oxidized phosphatidylcholine (PC-OX) are recognized by specific phagocyte receptors and contribute to the clearance of dying cells

Methodology Applied

Scientific EffectPhosphatidylserine recognition:

Implementation Method 2

engineered tether proteins link apoptotic cells to immunogenic receptors, thereby blocking homeostatic elimination of cells while simultaneously activating or disinhibiting immune pathways

Methodology Applied

Scientific EffectImmune receptor activation:

Implementation Method 3

Compositions and methods are provided for altering clearance mechanisms of cellular corpses to promote inflammatory turnover of apoptotic cells and enhance their immunogenicity

Methodology Applied

Scientific EffectInflammatory turnover:

Data Source

PatentUS10934331B2Methods for enhancing immune responsiveness in an individual toward a target cancer cell population comprising apoptotic cells

Publication Date: 2021.03.02 THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV

AI summary

Cell loss by apoptosis is a common feature in certain conditions, including cancer. Dying tumor cells induce immune tolerance within the tumor microenvironment largely through highly conserved homeostatic clearance programs that are designed to restore tissue homeostasis and contribute to the formation of an immunosuppressive niche. The translocation of phosphatidylserine (PS) on cellular membranes, during the initial phases of apoptosis, functions as a recognition and removal signal that limits the immunogenicity of cell death. To remove inhibitory signals in the homeostatic clearance pathway a fusion protein comprising a phosphatidylserine binding domain and an immunostimulatory domain can restore immune responses to dead tumor cells in antigen cross presentation assays and promotes recruitment and retention of tumor antigen specific immune effector cells into tumors. These effects combine to elicit anti-tumor immunity, improve responses to immune checkpoint inhibitors, and enhance the effectiveness of adoptive T cell transfers using engineered T cells.