Anti-ROR1 Antibody Formulation for High-Concentration Stability
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Solution Overview
Problem
Developing stable, highly concentrated pharmaceutical formulations of antibodies, particularly targeting ROR1, is challenging due to solubility and stability issues, limiting their administration via intravenous routes.
Innovation Solution
Formulations comprising antibodies or antigen-binding fragments at 20-80 mg/mL, with buffers like acetate, citrate, histidine, or phosphate, chelating agents like EDTA, surfactants like polysorbate 80, and trehalose dihydrate at 5.0% (w/v) or greater, maintained at a pH of 6.0 or lower, enhance stability and concentration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If antibody concentration is increased to improve therapeutic efficacy, then treatment effectiveness improves, but solubility and stability deteriorate leading to aggregation and precipitation
Solution Approach 1:
The patent applies parameter changes by systematically optimizing multiple formulation parameters including pH (adjusted to specific ranges using buffers), ionic strength, temperature, and the addition of stabilizing agents such as sugars, amino acids, and surfactants. These parameter modifications enable the formulation to maintain stability at high antibody concentrations by preventing aggregation and precipitation through controlled chemical and physical conditions.
Solution Approach 2:
The patent employs composite materials by combining the antibody with multiple excipients including buffers (e.g., phosphate, citrate), chelating agents (e.g., EDTA), surfactants (e.g., polysorbate 80), and stabilizing agents (e.g., trehalose, mannitol). This composite formulation approach creates a synergistic system where each component contributes to maintaining solubility and stability at high concentrations, with the buffer maintaining pH, the chelating agent sequestering metals, the surfactant preventing aggregation, and the stabilizing agent providing molecular protection.
2Quantity of substance
If intravenous infusion volume is increased to deliver higher antibody doses, then therapeutic effect improves, but patient tolerance and administration feasibility deteriorate
Solution Approach 1:
The patent applies parameter changes by formulating antibodies at extremely high concentrations (100-500 mg/mL or higher), which is a significant departure from conventional formulations. This parameter change in concentration enables the delivery of therapeutic doses in much smaller infusion volumes, thereby maintaining treatment effectiveness while improving patient tolerance and administration feasibility by reducing the burden of large-volume infusions.
3Stability of the object's composition
If pH is lowered to improve antibody stability, then formulation stability improves, but antibody activity and patient comfort deteriorate
Solution Approach 1:
The patent applies parameter changes by precisely controlling pH within specific ranges (e.g., pH 3.0-6.0 for certain antibodies, or pH 4.0-7.0 for others) rather than using extreme values. This optimized pH control, combined with the use of appropriate buffers and stabilizing agents, enables the formulation to maintain both stability and activity by preventing denaturation and aggregation while preserving the antibody's functional conformation and binding capability.
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 antibody purity and reduce aggregate formation, achieving at least 97% purity after 4 weeks at 40°C, suitable for treating cancers such as leukemia, lymphoma, and solid tissue cancers.
Implementation Method 1
5.0% (w/v) or greater of trehalose dihydrate
Implementation Method 2
trehalose dihydrate
Implementation Method 3
a buffer
Implementation Method 4
a chelating agent
Implementation Method 5
a surfactant
Data Source
AI summary
Provided herein are pharmaceutical compositions comprising: an anti-ROR1 antibody or ROR1-binding antibody fragment thereof; and about 5% (w/v) or greater trehalose; wherein the anti-ROR1 antibody or ROR1-binding antibody fragment thereof. The pharmaceutical compositions disclosed herein reduces the formation of aggregates, and maintains high purity of the antibody or antigen binding fragment thereof.