Antibody-Drug Conjugate Formulation pH Adjustment
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Solution Overview
Problem
Antibody-drug conjugates (ADCs) face limitations in clinical use due to their tendency to aggregate and reversibly self-associate, which reduces their efficacy and stability, leading to decreased potency and increased toxicity.
Innovation Solution
Formulating ADCs with a benzodiazepine, such as D5 or D5(a), at a pH between 4.0 and 4.5, along with a buffer like succinate and a sugar like trehalose, to reduce reversible self-association, and optionally including a surfactant like polysorbate 20 or a small hydrophobic molecule like betaine to inhibit aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ADCs are formulated at conventional pH levels (5.0-7.0), then the formulation is easier to prepare and handle, but reversible self-association occurs significantly, reducing efficacy and stability
Solution Approach 1:
The patent applies parameter changes by adjusting the pH of the formulation to a specific range of 4.0-4.5, which is lower than conventional pH levels. This pH adjustment fundamentally changes the electrostatic interactions between ADC molecules, reducing reversible self-association and improving stability and efficacy without significantly complicating the formulation process
2Reliability
If ADCs are formulated without aggregation inhibitors, then the formulation is simpler, but aggregation occurs, reducing clinical efficacy
Solution Approach 1:
The patent uses parameter changes by adjusting pH to 4.0-4.5 to prevent aggregation, eliminating the need for additional aggregation inhibitor excipients. This approach maintains clinical efficacy while keeping the formulation composition relatively simple
Solution Approach 2:
The patent introduces trehalose as an intermediary substance that stabilizes ADC monomers and prevents aggregation. Trehalose acts as a protective agent that mediates between the ADC molecules and the aqueous environment, preventing harmful interactions while maintaining formulation simplicity
3Reliability
If ADCs exhibit reversible self-association, then the formulation requires fewer stabilizing excipients, but the potency and therapeutic effectiveness decrease
Solution Approach 1:
The patent applies parameter changes by setting pH to 4.0-4.5, which reduces reversible self-association and maintains high potency. This allows the formulation to use minimal amounts of stabilizing excipients while preserving therapeutic effectiveness
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 significantly reduces reversible self-association by up to 90%, enhancing the stability and potency of ADCs, thereby improving their therapeutic effectiveness and safety by maintaining higher monomer levels and reducing viscosity.
Implementation Method 1
ADCs are able to aggregate to each other through various mechanisms, including covalent bonding and hydrophobic interactions
Implementation Method 2
WO 2015/075201 A1 describes surfactant free lyophilized formulations of antibody-drug conjugates
Data Source
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AI summary
This disclosure is directed to antibody-drug conjugates. More specifically, this disclosure is directed to compositions comprising (i) antibody-drug conjugates comprising benzodiazepines, and (ii) a small hydrophobic molecule, methods of treatment using the compositions, and methods of formulating the compositions. Furthermore, this disclosure is directed to methods of reducing reversible self-association in antibodies and in antibody-drug conjugates.