Non-Binding Protein-Drug Conjugates for Macropinocytosis-Selective Uptake
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Solution Overview
Problem
Existing therapeutics lack the ability to selectively target and internalize through enhanced macropinocytosis exhibited by pathological cells involved in disease processes, such as cancer and neurodegenerative diseases.
Innovation Solution
Development of non-binding protein-drug conjugates comprising a non-binding protein scaffold, a peptide linker, and a pharmaceutically active or diagnostic moiety, which are designed to have increased susceptibility to macropinocytosis in pathological cells, allowing targeted cellular uptake and delivery of therapeutic or diagnostic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapeutics are used, then they can be administered to patients, but they lack the ability to selectively target and internalize through enhanced macropinocytosis exhibited by pathological cells
Solution Approach 1:
The patent modifies the physical and chemical parameters of the therapeutic agent by conjugating it to a protein scaffold with specific properties (size, charge, hydrophobicity) that enable exploitation of the enhanced macropinocytosis pathway in pathological cells. This parameter change allows the conjugate to be selectively internalized by cells exhibiting macropinocytosis while conventional therapeutics are not.
2Reliability
If non-binding protein-drug conjugates are developed, then selective internalization through macropinocytosis is achieved, but the complexity of the therapeutic structure increases
Solution Approach 1:
The therapeutic conjugate is segmented into distinct functional modules: a non-binding protein scaffold that enables macropinocytosis, a peptide linker that provides stability and controlled release, and a pharmaceutically active moiety that delivers the therapeutic effect. This segmentation allows each component to be optimized independently while maintaining overall functionality.
Solution Approach 2:
The protein scaffold acts as an intermediary carrier that mediates the selective internalization of the therapeutic agent through macropinocytosis. The peptide linker serves as an intermediary that connects the scaffold to the active moiety while controlling the timing and location of drug release within the cellular environment.
Data Source
AI summary
Described herein are non-binding protein-drug conjugates having increased susceptibility to macropinocytosis by a population of cells in a macropinocytosis-positive disease state relative to a population of cells that are not in a macropinocytosis-positive disease state. The non-binding protein-drug conjugate can comprise a first portion comprising a non-binding protein scaffold that does not substantially bind to a cell surface, wherein the non-binding protein scaffold does not comprise a non-binding fibronectin type III (FN3) domain. A peptide linker can be coupled to and positioned between the first portion and a second portion, wherein the second portion can comprise a pharmaceutically active moiety or a diagnostic moiety.