Engineered Adnectin Proteins for EGFR Targeting

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current therapeutic options for targeting EGFR in cancers, such as breast and ovarian cancers, face challenges due to potential life-threatening side effects and limited tissue penetration of existing drugs, necessitating the development of novel EGFR binding polypeptides with improved biophysical properties and pharmacokinetics.

Innovation Solution

Design and development of polypeptides comprising fibronectin type III (Fn3) domains with altered amino acid sequences in specific loops for enhanced binding affinity to EGFR, combined with pharmacokinetic moieties like polyoxyalkylene for improved bioavailability and serum half-life, and potential use of additional domains for targeted therapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If monoclonal antibodies or small molecule inhibitors are used to target EGFR, then therapeutic efficacy is achieved, but side effects become severe or life-threatening

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the molecular parameters of the therapeutic agent by using engineered single-domain proteins (Adnectins) with specific binding characteristics. These proteins are designed to bind EGFR with high affinity while having different pharmacokinetic properties compared to traditional monoclonal antibodies or small molecule inhibitors, thereby achieving therapeutic efficacy with reduced side effects

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The engineered single-domain proteins are designed to be smaller and potentially shorter-lived in circulation compared to full monoclonal antibodies. This allows for more frequent dosing with smaller molecules that may have better tissue penetration and reduced immunogenicity, thus improving the side effect profile while maintaining therapeutic efficacy

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Reliability

If traditional EGFR inhibitors are used, then receptor binding is achieved, but tissue penetration is limited

Engineering Contradiction:

Improvereceptor bindingVSAvoidtissue penetration

Core Design Contradiction:

ReliabilityVSLength of moving object

Solution Approach 1:

The patent segments the traditional large monoclonal antibody structure into smaller single-domain proteins. Each Adnectin consists of a single fibronectin type III domain, making it much smaller (approximately 15 kDa) compared to full antibodies. This segmentation enables better tissue penetration while maintaining the ability to bind EGFR through engineered loop regions

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent transitions from three-dimensional large molecular structures (monoclonal antibodies) to smaller, more compact single-domain proteins. This dimensional reduction allows the therapeutic agents to penetrate deeper into tumor tissues and reach EGFR targets that may be inaccessible to larger molecules

Inventive Principle:

Principle #17Another dimension (Dimensionality change)

Data Source

PatentUS10781247B2Targeted therapeutics based on engineered proteins that bind EGFR

Publication Date: 2020.09.22 BRISTOL MYERS SQUIBB CO

AI summary

The present invention relates to single domain proteins that bind to epidermal growth factor receptor (EGFR). The invention also relates to single domain proteins for use in diagnostic, research and therapeutic applications. The invention further relates to cells comprising such proteins, polynucleotide encoding such proteins or fragments thereof, and to vectors comprising the polynucleotides encoding the innovative proteins.