PCSK9-Binding Fibronectin Compositions for High-Concentration Dosing
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Solution Overview
Problem
Existing monoclonal antibody formulations for PCSK9 inhibition face solubility limitations, increased viscosity, instability, and aggregation issues, necessitating higher volumes and less frequent dosing schedules, which are not patient-friendly.
Innovation Solution
Development of fibronectin scaffold proteins, specifically adnectins, with high affinity for PCSK9, chemically conjugated or genetically fused with human serum albumin (HSA), allowing stable formulation at high concentrations and convenient dosing schedules, suitable for subcutaneous, intramuscular, or intravenous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Volume of moving object
If higher concentration of active agent is used to reduce dosing volume, then dosing volume is reduced, but solubility limitations and increased viscosity occur
Solution Approach 1:
The patent changes the molecular structure parameters of the active agent from monoclonal antibody to fibronectin scaffold protein with HSA fusion, enabling higher solubility and lower viscosity at concentrated formulations (100-300 mg/mL), thus reducing dosing volume while maintaining stability
Solution Approach 2:
The patent creates a composite protein structure by fusing the PCSK9-binding fibronectin scaffold domain with human serum albumin (HSA), combining the high-affinity binding capability with the solubility and stability properties of HSA, enabling stable high-concentration formulations
2Volume of moving object
If higher concentration of active agent is used to reduce dosing volume, then dosing volume is reduced, but aggregation and particulate formation increase
Solution Approach 1:
The patent changes the physicochemical parameters of the active agent to fibronectin scaffold proteins with specific structural characteristics that remain stable at high concentrations (100-300 mg/mL) without aggregation or particulate formation, enabling reduced dosing volume while maintaining reliability
Solution Approach 2:
The patent employs a protein structure (fibronectin scaffold with HSA fusion) that is engineered for stability and resistance to degradation under storage and dosing conditions, ensuring the formulation remains reliable even at high concentrations required for volume reduction
3Reliability
If monoclonal antibody formulations are used, then PCSK9 inhibition is achieved, but dosing frequency is low and patient-friendliness is reduced
Solution Approach 1:
The patent changes the pharmacokinetic parameters by using fibronectin scaffold proteins with HSA fusion, which enable more frequent dosing schedules with smaller volumes, improving patient convenience while maintaining PCSK9 inhibition efficacy
Solution Approach 2:
The patent segments the dosing regimen into more frequent, smaller-volume administrations rather than less frequent large-volume injections, making the treatment more patient-friendly while achieving the same therapeutic effect
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 PCSK9-binding fusion proteins achieve maximum biological activity with reduced dosing volumes and frequencies, providing effective LDL-C reduction for treating hypercholesterolemia and atherosclerosis, even in statin-intolerant patients, with stable formulations that minimize degradation and particulate formation.
Implementation Method 1
PCSK9-binding molecules and methods of use... fibronectin-based scaffold domain proteins that bind proprotein convertase subtilisin kexin type 9 (PCSK9)... PCSK9 binds to the receptor for low-density lipoprotein particles (LDL)
Implementation Method 2
The PCSK9-binding fusion protein comprises a PCSK9-binding motif and an amino acid sequence of a human serum albumin (HSA)... which can be stably formulated at high concentrations for maximum biological effect... stable formulations that minimize degradation and particulate formation
Data Source
AI summary
The present disclosure provides pharmaceutical compositions comprising fibronectin based scaffold domain proteins that bind, for example, proprotein convertase subtilisin kexin-9 (PCSK9).