Surfactant-Free Antibody-Drug Conjugate Formulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current pharmaceutical formulations of antibodies and antibody-drug conjugates (ADCs), particularly those targeting AXL, face stability issues due to degradation, aggregation, and the need for surfactants like polysorbate, which can be toxic and lead to unstable products.
Innovation Solution
Development of lyophilized and aqueous formulations for anti-AXL antibodies and ADCs that are stable without surfactants, using buffers, non-reducing sugars, and bulking agents like mannitol to maintain stability during storage and transport.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If surfactants like polysorbate are used in antibody and ADC formulations to reduce aggregation and adsorption, then the stability of the antibody is improved, but the toxicity increases and the product becomes less stable due to oxidation and hydrogen peroxide formation
Solution Approach 1:
The patent removes surfactants from the formulation entirely, replacing them with alternative stabilizing agents such as amino acids (e.g., histidine, arginine) and sugars. This extraction of the harmful component (surfactant) eliminates the source of oxidation and toxicity while maintaining stability through the alternative agents.
Solution Approach 2:
The patent introduces amino acids and sugars as intermediary substances that mediate between the antibody and the environment. These intermediaries protect the antibody from aggregation and adsorption without the harmful oxidative effects of surfactants, acting as benign mediators in the formulation system.
2Stability of the object's composition
If surfactants are used in ADC formulations to prevent aggregation, then the physical stability is improved, but the chemical stability deteriorates due to oxidation of the antibody molecule
Solution Approach 1:
The patent converts the potential harm of oxidation into a benefit by using reducing agents (e.g., cysteine, glutathione) in the formulation. These agents scavenge any oxidizing species before they can damage the antibody, effectively converting the harmful oxidative environment into a protective reducing environment that maintains both physical and chemical stability.
Solution Approach 2:
The patent changes the chemical parameters of the formulation by adjusting pH, ionic strength, and redox potential through the selection of specific buffers and additives. These parameter changes create an environment that prevents both aggregation (physical instability) and oxidation (chemical instability) simultaneously.
3Reliability
If drug conjugation is performed on antibodies to create ADCs, then the therapeutic potency is improved, but the stability of the antibody structure deteriorates due to destabilization of the CH2 domain
Solution Approach 1:
The patent applies prior cushioning by including stabilizing agents (amino acids, sugars, and reducing agents) in the formulation before the ADC is subjected to storage or transport conditions. These agents pre-establish a protective environment that compensates for the inherent structural instability introduced by drug conjugation, preventing degradation before it can occur.
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, surfactant-free solutions that maintain the integrity of anti-AXL antibodies and ADCs, reducing degradation and aggregation, thus enhancing their efficacy and safety for cancer therapy.
Implementation Method 1
it was discovered that mannitol, which functions efficiently as a bulking agent for AXL-ADCs, functions efficiently as a stabilizer for the corresponding anti-AXL antibody
Implementation Method 2
The present inventors have discovered lyophilized formulations of anti-AXL antibody-drug conjugates
Data Source
AI summary
Disclosed herein are surfactant free antibody and antibody-drug-conjugate (ADC) formulations for anti-AXL antibodies and ADCs, including aqueous formulations, lyophilized formulations, and reconstituted formulations, as well as related processes and uses. The formulations are particularly suitable for an anti-AXL ADC based on an auristatin or DM1 derivative or other similarly hydrophobic drugs. Some formulations comprise histidine and mannitol.