PD-1 Antibody and PH20 Formulation for Low Oxidation Stability
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Solution Overview
Problem
Existing immune checkpoint therapies, such as pembrolizumab, face challenges due to methionine oxidation and deamidation in the CDR regions of PD-1 antibodies, impacting biological activity, and the need for effective co-administration with hyaluronidase like PH20 to enhance subcutaneous delivery.
Innovation Solution
Formulations of anti-PD-1 antibodies with controlled oxidation and deamidation, combined with PH20 variants, using a continuous perfusion process to enhance stability and activity, include buffers, non-reducing sugars, and optional antioxidants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pembrolizumab is produced using conventional methods, then production efficiency is achieved, but Met105 oxidation occurs reducing biological activity
Solution Approach 1:
The patent changes the production parameters by using a perfusion process instead of conventional batch culture, controlling cell density and nutrient supply to reduce oxidative stress and minimize Met105 oxidation while maintaining production efficiency
Solution Approach 2:
The patent creates a reduced oxygen environment during antibody production to minimize oxidation of Met105, effectively creating an inert atmosphere that protects the antibody from oxidative damage while maintaining biological activity
2Ease of operation
If subcutaneous administration is used for PD-1 antibodies, then patient convenience is improved, but hyaluronic acid in extracellular matrix limits delivery efficiency
Solution Approach 1:
The patent uses PH20 hyaluronidase as an intermediary enzyme that degrades hyaluronic acid in the subcutaneous extracellular matrix, clearing the path for improved antibody delivery while maintaining the convenience of subcutaneous administration
Solution Approach 2:
The patent co-administers PH20 hyaluronidase before or with the PD-1 antibody to pre-clear the hyaluronic acid barrier in the subcutaneous tissue, preparing the delivery pathway in advance for enhanced antibody absorption
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 low oxidation and deamidation levels, enhancing hyaluronidase activity and stability, improving the therapeutic efficacy of PD-1 antibodies when co-administered subcutaneously.
Implementation Method 1
Hyaluronidases are enzymes that degrade hyaluronic acid present in the extracellular matrix. Hyaluronidase hydrolyzes hyaluronic acid, thereby reducing the viscosity of hyaluronic acid in the extracellular matrix and increasing the permeability thereof into tissue
Implementation Method 2
Oxidation of methionine is one of the major degradation pathways in many protein pharmaceuticals. Methionine residues in proteins are susceptible to oxidation, resulting in the formation of methionine sulfoxide
Implementation Method 3
Deamidation of asparagine residues can lead to succinimide formation, which can then be converted to aspartate or isoaspartate
Data Source
AI summary
The invention provides pharmaceutical compositions of anti-PD-1 antibodies or antigen-binding fragments thereof with less than or equal to about 3.0% oxidation of Met105 in the CDRH3 heavy chain region, and PH20 variants or fragments thereof. The invention also provides pharmaceutical compositions comprising anti-PD-1 antibody main species and acidic species thereof, wherein the amount of acidic species is about 1.0-12.0%, and PH20 variants or fragments thereof.