Anti-PD-1 Antibody Formulation for Stable High-Concentration Delivery
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing antibody formulations for PD-1 targeting therapies face challenges in maintaining bioactivity, stability, and high concentration delivery, particularly for subcutaneous administration, due to issues like high viscosity, aggregation, and oxidation of methionine residues.
Innovation Solution
Formulations comprising anti-human PD-1 antibodies with specific stabilizers (e.g., sucrose, trehalose), buffers (histidine), surfactants (poloxamer 338), and antioxidants (L-methionine) that maintain bioactivity and reduce oxidation, allowing for high concentrations suitable for subcutaneous delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If high concentration of anti-PD-1 antibody is used for subcutaneous administration, then therapeutic efficacy is improved, but viscosity increases making delivery difficult
Solution Approach 1:
The patent applies parameter changes by modifying the physical and chemical properties of the formulation through specific excipients. The inclusion of 0.05-0.5% polysorbate 80, 0.1-10% sucrose, and pH adjustment to 5.0-7.0 changes the rheological parameters of the solution, reducing viscosity and improving deliverability while maintaining high antibody concentration (10-100 mg/mL) for effective subcutaneous administration
Solution Approach 2:
The patent uses surfactants (polysorbate 80) and sugars (sucrose) as intermediary substances that mediate between the antibody molecules. These intermediaries prevent protein-protein interactions that lead to aggregation and viscosity increase, allowing high concentration delivery without compromising injectability
2Quantity of substance
If high concentration of anti-PD-1 antibody is formulated, then dosage volume is reduced, but aggregation increases reducing stability
Solution Approach 1:
The patent employs sucrose (0.1-10%) and polysorbate 80 (0.05-0.5%) as intermediary molecules that physically separate antibody molecules at high concentrations. These intermediaries form protective layers around the antibodies, preventing aggregation and maintaining formulation stability even at 10-100 mg/mL concentrations
Solution Approach 2:
The patent creates an inert molecular environment by using surfactants and sugars that form a protective matrix around the antibodies. This inert environment prevents harmful protein-protein interactions and oxidative damage, maintaining stability at high concentrations
3Reliability
If methionine residues are present in the antibody sequence, then binding affinity is improved, but oxidation occurs reducing bioactivity
Solution Approach 1:
The patent converts the harmful effect of methionine oxidation into a beneficial outcome by using antioxidants (ascorbic acid 0.1-10% or tocopherol 0.01-1%) to scavenge oxidizing species. The methionine residues maintain their binding affinity function while the antioxidants prevent oxidation, effectively converting a potential harm into a controlled system where both properties coexist
Solution Approach 2:
The patent introduces antioxidant molecules as intermediaries between the methionine residues and oxidizing agents. These intermediary antioxidants (ascorbic acid or tocopherol) preferentially react with oxidizing species, protecting the methionine residues in the antibody from oxidation while allowing the methionine to maintain its binding function
4Ease of manufacture
If conventional formulations are used, then manufacturing is simplified, but shelf-life is insufficient for clinical use
Solution Approach 1:
The patent applies parameter changes by optimizing pH (5.0-7.0), adding stabilizing excipients (sucrose 0.1-10%, polysorbate 80 0.05-0.5%), and incorporating antioxidants. These parameter modifications extend shelf-life to at least 6 months at 2-8°C and 1 month at room temperature while maintaining manufacturing simplicity through a single-step formulation process
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 formulations provide stable, high-concentration anti-PD-1 antibody solutions with reduced viscosity and aggregation, ensuring effective subcutaneous delivery and maintaining therapeutic efficacy by minimizing methionine oxidation.
Implementation Method 1
d) a surfactant selected from about 0.005% w/v to about 0.60% w/v non-ionic surfactant and about 0.23% w/v to about 1.15% w/v ionic surfactant
Implementation Method 2
e) about 1 mM to about 30 mM anti-oxidant
Implementation Method 3
minimizing methionine oxidation
Implementation Method 4
c) about 1.5 to about 8.0% weight/volume (w/v) stabilizer selected from the group consisting of: a non-reducing sugar, (2-hydroxypropyl)-β-cyclodextrin, mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, a pharmaceutically acceptable salt of L-proline, L-histidine, a pharmaceutically acceptable salt of L-histidine, glycine, or a pharmaceutically acceptable salt of glycine
Data Source
AI summary
The invention relates to stable formulations of antibodies against human programmed death receptor PD-1, or antigen binding fragments thereof. In some embodiments the formulations of the invention comprise between 5-250 mg/mL anti-PD-1 antibody, or antigen binding fragment thereof, a buffer, a stabilizer, a surfactant, and an antioxidant in the amounts specified herein. In particular embodiments, the anti-PD-1 antibody is pembrolizumab. The invention further provides methods for treating various cancers with stable formulations of the invention. In some embodiments of the methods of the invention, the formulations are administered to a subject by intravenous or subcutaneous administration.