Anti-PD-1 Antibody Formulation for Stable High-Concentration Injection
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Solution Overview
Problem
Existing anti-human PD-1 antibody formulations face challenges in maintaining bioactivity, stability, and high concentration delivery, particularly for subcutaneous administration, due to issues like high viscosity, aggregation, and methionine oxidation.
Innovation Solution
Formulations comprising anti-human PD-1 antibodies with specific buffers, stabilizers, and antioxidants, such as sucrose, trehalose, and polysorbate 80, along with pH control, reduce methionine oxidation and aggregation, ensuring stability and high concentration delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If high concentration of anti-PD-1 antibody is formulated for subcutaneous administration, then delivery efficiency is improved, but viscosity increases making injection difficult
Solution Approach 1:
The patent applies parameter changes by optimizing the formulation composition including pH adjustment (pH 5.0-6.5), selecting specific stabilizers (sucrose, trehalose, mannitol at defined concentrations), adding non-ionic surfactants (polysorbate 80, polysorbate 20), and controlling ionic strength to reduce antibody aggregation and viscosity, enabling high concentration formulations to be injected comfortably
Solution Approach 2:
The patent uses intermediary substances including stabilizers (sucrose, trehalose, mannitol), non-ionic surfactants (polysorbate 80, polysorbate 20), and buffers (histidine, acetate) that mediate between the high concentration antibody and the injection system, reducing intermolecular interactions and viscosity to enable smooth injection
2Duration of action of stationary object
If antibody is stored and transported in formulation, then bioactivity is maintained over time, but stability challenges arise from oxidation and aggregation
Solution Approach 1:
The patent applies preliminary anti-action by incorporating antioxidants (methionine, ascorbic acid, sodium metabisulfite) and stabilizers (sucrose, trehalose, mannitol) into the formulation before storage, which preemptively counteract oxidation and aggregation processes, maintaining antibody bioactivity during storage and transport
Solution Approach 2:
The patent creates an inert environment through formulation components including antioxidants that scavenge oxygen, buffers that maintain stable pH, and surfactants that prevent protein-protein interactions, effectively isolating the antibody from degrading influences during storage
3Reliability
If methionine residues are present in antibody sequence, then biological function is maintained, but oxidation of methionine occurs reducing bioactivity
Solution Approach 1:
The patent converts the potential harm of methionine oxidation into a benefit by using methionine itself as an antioxidant in the formulation, where excess methionine sacrifices itself to protect the antibody's critical methionine residues from oxidation, maintaining bioactivity
Solution Approach 2:
The patent uses intermediary antioxidants including methionine, ascorbic acid, and sodium metabisulfite that act as sacrificial protectors, absorbing oxidative damage before it reaches the antibody's critical methionine residues, thereby preserving biological function
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 maintain bioactivity and reduce oxidation of methionine residues, providing stable and injectable high-concentration antibody solutions for subcutaneous use.
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
Implementation Method 3
about 1.8 to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof
Implementation Method 4
about 0.01% to about 0.10% non-ionic surfactant
Implementation Method 5
about 1 mM to about 20 mM anti-oxidant
Implementation Method 6
about 5 mM to about 20 mM buffer
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.