Risankizumab Composition With Reduced PLA2 for Stable Formulation
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Solution Overview
Problem
Risankizumab formulations are affected by hitchhiker proteins, particularly phospholipase A2 (PLA2), which degrade polysorbate and lead to particle formation, reducing stability and shelf-life, and also exhibit immunogenicity due to high mannose N-glycans.
Innovation Solution
Formulations with reduced PLA2 levels and the use of poloxamer 188 instead of polysorbate, along with optimized purification processes, to minimize hitchhiker proteins and improve stability and immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If polysorbate 20 is used as a surfactant in risankizumab formulations, then the formulations can be prepared with standard purification processes, but trace amounts of hitchhiker proteins (particularly PLA2) cause polysorbate hydrolysis leading to particle formation and reduced shelf life
Solution Approach 1:
The patent applies the extraction principle by removing the problematic hitchhiker proteins (particularly PLA2) from the risankizumab formulation through enhanced purification processes. This extraction of harmful components eliminates the cause of polysorbate hydrolysis and particle formation, thereby resolving the contradiction between ease of manufacture and formulation stability.
Solution Approach 2:
The patent applies parameter changes by modifying the purification process parameters to achieve lower levels of hitchhiker proteins. By changing the purification conditions and parameters, the formulation achieves sufficient purity to prevent polysorbate degradation while maintaining manufacturability, thus resolving the stability-ease of manufacture contradiction.
2Ease of manufacture
If standard purification processes are used for risankizumab production, then the manufacturing process is simple and cost-effective, but hitchhiker proteins co-purify with the monoclonal antibody leading to formulation instability
Solution Approach 1:
The patent converts the harmful co-purification behavior into a beneficial selective removal process. By identifying specific hitchhiker proteins that co-purify with risankizumab under standard conditions, the invention develops targeted purification steps that exploit these interaction patterns to selectively remove the harmful proteins while retaining the therapeutic antibody, thus transforming a manufacturing challenge into a solution.
Solution Approach 2:
The patent modifies purification process parameters to change the selectivity of protein separation. By adjusting parameters such as pH, ionic strength, or column conditions, the process achieves differential purification that removes hitchhiker proteins while maintaining high recovery of risankizumab, resolving the contradiction between manufacturing simplicity and impurity reduction.
3Quantity of substance
If high concentrations of risankizumab are formulated (e.g., 150 mg/mL), then the dosing volume is reduced and patient compliance improves, but the formulations become more susceptible to particle formation from polysorbate hydrolysis
Solution Approach 1:
The patent applies extraction by removing the catalyst (hitchhiker proteins) that triggers polysorbate hydrolysis. This elimination of the harmful component allows high-concentration formulations to be stabilized, as the remaining formulation lacks the enzymes that would otherwise cause particle formation even at elevated antibody concentrations.
Solution Approach 2:
The patent creates a composite formulation system where highly purified risankizumab is combined with stabilized surfactant systems. By integrating multiple purified components and optimizing their interactions, the formulation achieves both high concentration and enhanced stability, resolving the contradiction between quantity and reliability.
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
Increased stability and reduced immunogenicity of risankizumab formulations, with decreased particle formation and lower anti-drug antibody incidence.
Implementation Method 1
trace amounts of hitchhiker protein contaminants in preparations of certain recombinantly produced biologic pharmaceutical products can cause polysorbate 20 hydrolysis leading to particle formation
Implementation Method 2
the primary sequence of a mAb may be responsible for the binding and consequence co-purification of the specific hitchhiker protein
Data Source
AI summary
The present disclosure relates, in part, to risankizumab compositions having a reduced level of hitchhiker protein PLA2, Poloxamer 188, and/or decreased immunogenicity.