PSGL-1 Anionic Domain Fusion Antibodies for Tumor Targeting

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Solution Overview

Problem

Current immune checkpoint modulation therapies for cancer treatment, such as those using checkpoint-modulating antibodies, face limitations in enhancing tumor killing and anti-metastatic activities within the tumor microenvironment, particularly in effectively targeting and modulating the interactions between selectins and their ligands like PSGL-1.

Innovation Solution

Fusion proteins are created by combining a single anionic domain of PSGL-1 or multiple tandem anionic domains (TSGL) with checkpoint-modulating antibodies, enhancing their binding activities and antigen recognition capabilities, thereby improving their anti-cancer efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If checkpoint-modulating antibodies are used alone, then they can stimulate T-cell activation or block inhibitory signals, but their tumor killing and anti-metastatic activities are limited within the tumor microenvironment

Engineering Contradiction:

Improvetumor killing activityVSAvoidability to target selectin-PSGL-1 interactions

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent combines checkpoint-modulating antibodies with PSGL-1 anionic domains to create fusion proteins that simultaneously provide checkpoint modulation and selectin ligand binding capabilities, thereby enhancing tumor targeting and anti-metastatic activity while maintaining T-cell activation functions

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The fusion proteins represent composite molecular structures combining antibody components with PSGL-1 anionic domain sequences, creating a hybrid molecule with dual functionality for checkpoint modulation and enhanced tumor microenvironment targeting

Inventive Principle:

Principle #40Composite materials

2Reliability

If checkpoint-modulating antibodies are used, then they can overcome self-tolerance regulatory mechanisms, but their anti-metastatic activity is insufficient

Engineering Contradiction:

Improveanti-metastatic activityVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges checkpoint-modulating antibody functionality with PSGL-1 anionic domain sequences into single fusion proteins, thereby achieving both anti-metastatic activity and checkpoint modulation without requiring separate molecular entities or complex combination therapies

Inventive Principle:

Principle #5Merging (Combining)

3Object-affected harmful factors

If selectin-mediated cellular adhesion is blocked, then tumor cell metastatic spread may be reduced, but the ability to recruit immune cells to tumor microenvironment may be affected

Engineering Contradiction:

Improvemetastatic spreadVSAvoidimmune cell recruitment

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The PSGL-1 anionic domain fusion proteins act as intermediaries that can bind to selectins while simultaneously engaging checkpoint-modulating antibodies, thereby modulating selectin-mediated adhesion in a controlled manner that reduces metastasis while potentially preserving beneficial immune cell recruitment functions

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The fusion proteins exert localized effects on selectin-PSGL-1 interactions within the tumor microenvironment, selectively interfering with metastatic adhesion pathways while allowing immune cell recruitment processes to proceed through alternative or unaffected mechanisms

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20230303657A1Fusion Molecules of PSGL-1 or TSGL Anionic Domains to Checkpoint-Modulating Antibodies and Other Antibodies

Publication Date: 2023.09.28 SHAW GRAY D

AI summary

Therapeutic immune checkpoint modulating antibodies, such as anti-PD-1 and anti-CTLA-4 antibodies, therapeutic cancer antibodies or anti-viral antibodies, are fused with the anionic domain of P-selectin glycoprotein ligand-1 (PSGL-Abs) or tandem anionic domains of P-selectin glycoprotein ligand-1 (TSGL-Abs) to enhance their therapeutic activities. PSGL-Abs or TSGL-Abs can be designed to bind selectins or lack selectin binding.