Bispecific Antibody Formulation for pH-Stable Anti-PD-L1/4-1BB
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Solution Overview
Problem
Formulating stable pharmaceutical preparations for anti-PD-L1/anti-4-1BB bispecific antibodies is challenging due to their complex structure and instability, which can lead to degradation and immune responses, necessitating a formulation that maintains conformational integrity and stability.
Innovation Solution
Aqueous formulations with specific pH ranges (5.0 to 6.5) and compositions including acetate acid/sodium acetate buffers, arginine, trehalose, and polysorbate 80 are developed to stabilize anti-PD-L1/anti-4-1BB bispecific antibodies, preventing decomposition and aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibodies are used in pharmaceutical formulations, then therapeutic effect is achieved, but conformational integrity and stability are compromised due to degradation and aggregation
Solution Approach 1:
The patent applies parameter changes by optimizing the pH value (5.0-6.5) and ionic strength (100-300 mM) of the formulation to maintain antibody stability. By adjusting these physical-chemical parameters, the formulation prevents degradation and aggregation while preserving conformational integrity and biological activity.
Solution Approach 2:
The patent uses arginine (10-200 mM) and trehalose (10-300 mM) as intermediary substances that act as stabilizing agents. These excipients mediate between the antibody and the formulation environment, preventing direct harmful interactions and maintaining protein structure through molecular shielding and hydration effects.
2Stability of the object's composition
If excipients are added to stabilize antibodies, then conformational integrity is maintained, but potential immune responses increase
Solution Approach 1:
The patent selects specific concentration ranges for excipients (arginine: 10-200 mM, trehalose: 10-300 mM, polysorbate 80: 0.01-10 mg/ml) to optimize stability while minimizing immunogenicity. By precisely controlling these parameters, the formulation achieves protective effects without triggering excessive immune responses.
Solution Approach 2:
The patent employs commonly used, well-characterized excipients with established safety profiles. These excipients are selected for their proven track record in pharmaceutical formulations, balancing stability benefits with acceptable safety characteristics and minimal immune reactivity.
3Reliability
If buffer systems are used to control pH, then stability is improved, but formulation complexity increases
Solution Approach 1:
The patent employs simple buffer systems (acetate buffer, phosphate buffer) with straightforward composition and adjustment procedures. These buffers effectively control pH within the optimal range (5.0-6.5) without introducing complex multi-component systems, thereby maintaining formulation simplicity while ensuring stability.
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 long-term stability and maintain biological activity of anti-PD-L1/anti-4-1BB bispecific antibodies, ensuring effective cancer treatment with minimal immune response.
Implementation Method 1
the formulation has a pH of about 5.0 to about 6.5... the buffer comprises a buffering agent selected from the group consisting of acetic acid, sodium acetate, tartrate, hydrogen chloride, sodium dihydrogen phosphate, and combinations thereof... the formulation comprises an acetate acid/sodium acetate buffer with a concentration of about 10 mM to about 100 mM
Implementation Method 2
the formulation further comprises a tonicity agent selected from the group consisting of trehalose, sucrose, proline, glycine, arginine, alanine, glutamate, methionine, sodium chloride, potassium chloride, magnesium chloride, sodium sulfate and combinations thereof... the formulation comprises from about 10 mM to about 200 mM of arginine... the formulation comprises from about 10 mM to about 300 mM of trehalose
Implementation Method 3
the formulation further comprises a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, SDS, poloxamer 188 (Pluronic® F68), and combinations thereof... the surfactant is polysorbate 80... the formulation comprises from about 0.01 mg/ml to about 10 mg/ml polysorbate 80
Data Source
AI summary
Provided are formulations for anti-PD-L1/anti-4-1BB bispecific antibodies and methods of making and using the same. In one aspect, the disclosure relates to a stable aqueous pharmaceutical formulation comprising an anti-PD-L1/anti-4-1BB bispecific antibody or antigen-binding fragment thereof.