SPAM Peptides for PD-L1 Binding and Tumor Penetration

Solution Overview

Problem

Current PD-L1 targeting therapies face limitations due to high cost, low tumor penetration, and adverse immune-related events, with existing tests relying on single biopsy specimens that may not represent systemic PD-L1 expression levels, necessitating a more effective and accessible molecular scaffold for PD-L1-based therapeutics and diagnostics.

Innovation Solution

Designing novel, 18-22 residue linear peptides using mRNA display that selectively bind to human PD-L1 (SPAM peptides) with improved tumor penetration and affinity, competing with therapeutic antibodies, and exhibiting stability in human serum, while being easily synthesized and having a short half-life.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If monoclonal antibodies are used to block PD-L1/PD-1 interaction, then therapeutic efficacy is improved, but cost increases and tumor penetration decreases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidcost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent employs small peptides instead of expensive monoclonal antibodies to block the PD-L1/PD-1 interaction. These peptides are significantly cheaper to produce and manufacture, addressing the high cost issue while maintaining therapeutic efficacy through their ability to bind PD-L1 and prevent immune checkpoint activation.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent divides the large monoclonal antibody into smaller peptide fragments that can effectively bind to PD-L1. This segmentation into smaller units improves tumor penetration capability while retaining the essential blocking function, allowing the therapeutic agent to reach and act within tumor tissues more effectively.

Inventive Principle:

Principle #1Segmentation

2Reliability

If monoclonal antibodies are used to block PD-L1/PD-1 interaction, then therapeutic efficacy is improved, but tumor penetration decreases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtumor penetration

Core Design Contradiction:

ReliabilityVSLength of moving object

Solution Approach 1:

The patent divides the large monoclonal antibody into smaller peptide fragments that can effectively bind to PD-L1. This segmentation into smaller units improves tumor penetration capability while retaining the essential blocking function, allowing the therapeutic agent to reach and act within tumor tissues more effectively.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent changes the molecular size parameter from large monoclonal antibodies to small peptides. This parameter change enables better diffusion and penetration into tumor masses while maintaining the ability to block the PD-L1/PD-1 interaction and restore anti-tumor immunity.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If monoclonal antibodies are used for PD-L1 blockade, then immune checkpoint inhibition is achieved, but immune-related adverse events increase

Engineering Contradiction:

Improveimmune checkpoint inhibitionVSAvoidimmune-related adverse events

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs small peptides instead of expensive monoclonal antibodies to block the PD-L1/PD-1 interaction. These peptides are significantly cheaper to produce and manufacture, addressing the high cost issue while maintaining therapeutic efficacy through their ability to bind PD-L1 and prevent immune checkpoint activation.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

4Ease of operation

If existing PD-L1 tests are performed on single biopsy specimens, then diagnostic simplicity is maintained, but measurement precision decreases

Engineering Contradiction:

Improvediagnostic simplicityVSAvoidPD-L1 expression assessment

Core Design Contradiction:

Ease of operationVSMeasurement precision

Solution Approach 1:

The patent develops peptide-based agents that can serve multiple functions including therapy, imaging, and diagnostics. This multi-functionality allows for more comprehensive PD-L1 assessment beyond single biopsy specimens, potentially enabling systemic evaluation while maintaining operational simplicity through versatile peptide molecules.

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

The SPAM peptides demonstrate high selectivity and affinity for human PD-L1, inhibiting the PD-L1/PD-1 interaction, and show potential as a novel molecular scaffold for improved therapeutic and diagnostic applications, offering enhanced tumor penetration and stability compared to existing antibodies.

Implementation Method 1

The SPAM peptide binds both non-glycosylated hPD-L1 and glycosylated hPD-L1 (denoted hPD-L1*) with a KD of 119 nM and 67 nM, respectively

Methodology Applied

Scientific EffectProtein-protein binding interaction:

Data Source

PatentUS20230174616A1PD-l1 binding peptides

Publication Date: 2023.06.08 UNIV OF SOUTHERN CALIFORNIA

AI summary

The disclosure provides synthetic peptides that selectively bind to the PD-L1 protein on the surface of cells expressing PD-L1. The PD-L1 binding peptide may comprises the amino acid sequence MX1X2X3X4DHX5LNKFX6IX7HX8X9X10X11X12X13 (SEQ ID NO: 177) or MXIFπXXIXXXΩWXLXXA (SEQ ID NO: 1). Peptides of the disclosure may be functionalized using one or more diagnostic agents to aid in various detection modalities or with a cytotoxic agent to treat various disease states such as cancer. Also provided are compositions that include the PD-L1 binding peptides or functionalized PD-L1 binding peptides.