Anti-PD-1 Antibody Formulation for High-Concentration SC Injection
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing anti-human PD-1 antibody formulations face challenges with stability, high viscosity, aggregation, and methionine oxidation, particularly at high concentrations, which affect their bioactivity and administration efficacy.
Innovation Solution
Formulations comprising specific buffers, stabilizers, and antioxidants, such as sucrose, trehalose, and polysorbate 80, along with histidine and methionine, are developed to maintain antibody stability and reduce oxidation, ensuring high concentration and low viscosity for subcutaneous delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If anti-PD-1 antibody concentration is increased to reduce administration volume, then dosage efficiency is improved, but viscosity increases making subcutaneous injection difficult
Solution Approach 1:
The patent modifies formulation parameters including pH (adjusted to specific ranges using buffers like histidine or acetate), ionic strength, and temperature conditions to optimize the balance between antibody concentration and viscosity. These parameter changes enable high concentration formulations to maintain acceptable viscosity for subcutaneous injection.
Solution Approach 2:
The patent introduces intermediary substances including specific buffers (histidine, acetate), stabilizers (sucrose, trehalose, polysorbate 80), and viscosity-reducing agents that mediate between the antibody molecules to prevent excessive aggregation and maintain fluidity at high concentrations, thereby enabling both high dosage efficiency and feasible injection.
2Duration of action of stationary object
If storage time is extended to ensure adequate supply, then availability is improved, but antibody stability deteriorates due to degradation
Solution Approach 1:
The patent applies preliminary protective measures by incorporating antioxidants (such as methionine, ascorbic acid) and stabilizers (sucrose, trehalose, polysorbate 80) into the formulation before storage. These agents preemptively counteract oxidation and degradation processes, allowing the antibody to maintain stability throughout extended storage periods.
Solution Approach 2:
The patent creates an inert chemical environment within the formulation by using antioxidants that scavenge reactive oxygen species and buffers that maintain stable pH conditions. This inert chemical atmosphere protects the antibody from oxidation and hydrolysis during storage, preserving reliability over time.
3Reliability
If formulation components are added to prevent oxidation, then antibody stability is improved, but formulation complexity increases
Solution Approach 1:
The patent selects formulation components that perform multiple functions simultaneously. For example, histidine serves as both a buffer to maintain pH and an antioxidant to prevent oxidation; sucrose and trehalose provide both stabilization against aggregation and protection against oxidation. This multi-functionality reduces the number of separate additives needed, thereby limiting the increase in formulation complexity while maintaining oxidation resistance.
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 antibodies with reduced methionine oxidation and acceptable viscosity, facilitating effective subcutaneous administration and maintaining therapeutic efficacy.
Implementation Method 1
a stabilizer selected from the group consisting of: (i) about 6% to about 8% weight/volume (w/v) sucrose, trehalose or (2-hydroxypropyl)-β-cyclodextrin
Implementation Method 2
about 3% to about 5% w/v mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; and (iii) about 1.8 to about 2.2% w/v glycine
Implementation Method 3
about 0.01% to about 0.10% non-ionic surfactant
Implementation Method 4
about 1 mM to about 20 mM anti-oxidant
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 5-200 mg/mL anti-PD-1 antibody, or antigen binding fragment thereof. 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.