Anti-PD-L1 Antibody Formulation for Subcutaneous Injection
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Solution Overview
Problem
Current pharmaceutical formulations for subcutaneous administration of anti-PD-L1 antibodies are limited by low concentration and stability issues, leading to immunogenicity and reduced therapeutic efficacy due to aggregation, and there is a lack of suitable high-concentration, stable formulations for subcutaneous use.
Innovation Solution
A liquid pharmaceutical formulation comprising a monoclonal anti-PD-L1 antibody at concentrations of 100-150 g/L, histidine acetate, sucrose, polysorbate, and recombinant human hyaluronidase, with specific amino acid sequences and pH ranges, which maintains stability and biological activity for extended periods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the concentration of anti-PD-L1 antibody is increased for subcutaneous injection, then the therapeutic dose and volume are improved, but the formulation stability and aggregation behavior deteriorate
Solution Approach 1:
The patent applies parameter changes by optimizing multiple formulation parameters including pH (adjusted to specific ranges), ionic strength, buffer composition, and excipient concentrations to enable high antibody concentrations (up to 150 mg/mL) while maintaining formulation stability and preventing aggregation
Solution Approach 2:
The patent uses composite materials by combining the anti-PD-L1 antibody with a specific mixture of excipients including buffers (histidine, acetate), surfactants (polysorbate 20, poloxamer 188), and sugars (sucrose, trehalose) to create a stable high-concentration formulation suitable for subcutaneous injection
2Quantity of substance
If the concentration of anti-PD-L1 antibody is increased for subcutaneous injection, then the therapeutic efficacy is improved, but the immunogenicity increases due to aggregate formation
Solution Approach 1:
The patent controls aggregation and immunogenicity by precisely controlling formulation parameters including pH, ionic strength, and excipient concentrations, which prevents aggregate formation even at high antibody concentrations, thereby reducing immunogenicity while maintaining therapeutic efficacy
Solution Approach 2:
The patent includes hyaluronidase enzyme in the formulation to temporarily increase interstitial space for better antibody distribution and reduced aggregation risk, with the enzyme being inactivated after administration, providing a transient beneficial effect without long-term presence
3Quantity of substance
If the volume of injection is increased for subcutaneous administration, then the therapeutic dose is improved, but the injection resistance and backpressure increase
Solution Approach 1:
The patent changes the physical parameters of the formulation including viscosity, osmolarity, and pH to optimize the balance between delivering high therapeutic doses and minimizing injection resistance and backpressure in subcutaneous tissue
Solution Approach 2:
The patent uses hyaluronidase enzyme as an intermediary to temporarily degrade hyaluronic acid in the subcutaneous tissue, increasing interstitial space and facilitating easier injection of higher volumes with reduced backpressure
4Quantity of substance
If the concentration of anti-PD-L1 antibody is increased, then the number of injections required is reduced, but the manufacturing complexity increases
Solution Approach 1:
The patent optimizes multiple formulation parameters including buffer composition, pH, ionic strength, and excipient concentrations to achieve high antibody concentrations while maintaining stability, requiring sophisticated formulation development but enabling reduced injection frequency
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 formulation provides a stable and highly concentrated anti-PD-L1 antibody solution that retains biological activity, allowing for effective subcutaneous administration and prolonged storage, addressing the limitations of existing formulations by enhancing stability and reducing immunogenicity.
Implementation Method 1
it has been proposed to use glycosaminoglycanase enzyme(s) in order to increase the interstitial space into which the antibody formulation can be injected
Implementation Method 2
sucrose in a concentration of about 200 mM to about 280 mM
Implementation Method 3
polysorbate in a concentration of about 0.04% (w/v) to about 0.08% (w/v)
Implementation Method 4
histidine acetate in a concentration of about 15 mM to about 25 mM, and pH of about 5.6 to about 6.0
Data Source
AI summary
The invention provides liquid pharmaceutical formulations comprising an anti-PD-L1 antibody, such as liquid pharmaceutical formulations for subcutaneous administration. The invention also provides methods for making such formulations and methods of using such formulations.