PH20 Variant Composition for Stable High-Dose Subcutaneous Delivery
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Solution Overview
Problem
Current subcutaneous administration of high-dose drugs, particularly antibody drugs, is hindered by low absorption rates and potential swelling at the injection site, while intravenous administration is inconvenient and costly, and existing recombinant human PH20 proteins suffer from low stability and immunogenicity issues.
Innovation Solution
A pharmaceutical composition comprising a PH20 variant with specific amino acid substitutions and truncations in the alpha-helix 8 region and linker region, enhancing enzymatic activity and thermal stability, allowing for stable subcutaneous delivery of drugs like anti-HER2 antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If subcutaneous injection of high-dose drugs is performed, then drug delivery amount is increased, but absorption rate decreases and swelling occurs at injection site
Solution Approach 1:
The patent introduces hyaluronidase as an intermediary enzyme that hydrolyzes hyaluronic acid in the extracellular matrix, creating a pathway that enhances drug absorption. This mediator substance facilitates the transport of drugs from the injection site into the bloodstream, resolving the contradiction between delivering high doses and maintaining reliable absorption rates.
2Reliability
If intravenous injection is performed, then absorption rate is improved, but administration time increases and additional preparation is required
Solution Approach 1:
The patent modifies the administration route parameter from intravenous to subcutaneous while using hyaluronidase to change the local tissue environment. This parameter change allows subcutaneous injection to achieve absorption rates comparable to intravenous administration, thereby reducing administration time and eliminating the need for additional preparation procedures.
3Power
If animal-derived hyaluronidase is used, then enzymatic activity is achieved, but immunogenicity and allergic reactions occur
Solution Approach 1:
The patent creates a recombinant human hyaluronidase protein that copies the functional characteristics of natural human PH20 enzyme while eliminating the immunogenicity associated with animal-derived enzymes. This molecular copying approach produces an enzyme with human-specific amino acid sequences, ensuring compatibility with the human immune system while maintaining full enzymatic activity.
4Object-generated harmful factors
If recombinant human PH20 is used, then immunogenicity is reduced, but thermal stability and enzymatic activity are insufficient
Solution Approach 1:
The patent introduces specific amino acid substitutions at critical positions in the hyaluronidase protein structure, particularly in the alpha-helix 8 region and linker region. These localized modifications enhance the protein's thermal stability and enzymatic activity while preserving its human origin and low immunogenicity characteristics.
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 PH20 variant maintains drug activity and stability for extended periods, facilitating efficient subcutaneous administration with reduced swelling and immunogenicity, thus overcoming the limitations of current delivery methods.
Implementation Method 1
hyaluronic acid distributed in the extracellular matrix is hydrolyzed by the action of hyaluronidase, and thus the viscosity of the subcutaneous area decreases and the permeability of a substance increases
Data Source
AI summary
The present invention relates to a pharmaceutical composition including (a) a drug and (b) a human PH20 variant. The human PH20 variant included in the pharmaceutical composition according to the present invention comprises amino acid residue substitution(s) in one or more regions selected from an alpha-helix 8 region (S347 to C381) and a linker region (A333 to R346) between alpha-helix 7 and alpha-helix 8 in wild-type human PH20 having the amino acid sequence of SEQ ID NO: 1, wherein amino acid residue(s) located at the N-terminus or the C-terminus is(are) selectively truncated. In addition, the pharmaceutical composition according to the present invention may further comprise a pharmaceutically acceptable additive, particularly a stabilizer. The pharmaceutical composition according to the present invention can maximize the therapeutic effect of a drug used in combination therewith, due to the effect of human PH20 variants.