PAPPA Binding Proteins for ADPKD Cyst Growth Inhibition
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Solution Overview
Problem
Current treatments for autosomal dominant polycystic kidney disease (ADPKD), such as tolvaptan, are associated with tolerability issues and liver safety concerns, necessitating the development of new therapeutic approaches.
Innovation Solution
Development of pregnancy-associated plasma protein-A (PAPPA) binding proteins that inhibit the cleavage of insulin-like growth factor binding proteins (IGFBP-2, -4, and -5) by PAPPA, offering improved pharmacokinetic and pharmacodynamic properties with reduced non-specific binding and self-association, thereby potentially reducing kidney cyst growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If tolvaptan is used to treat ADPKD, then kidney cyst growth is reduced, but liver safety concerns and tolerability issues arise
Solution Approach 1:
The patent extracts and targets the specific molecular mechanism (PAPPA-IGFBP axis) responsible for cyst growth, rather than using broad-acting vasopressin antagonists. By designing antibodies that specifically bind PAPPA and inhibit its proteolytic activity, the treatment achieves cyst growth reduction through a different pathway that does not involve the liver toxicity mechanisms of tolvaptan
Solution Approach 2:
The patent changes the therapeutic parameter from vasopressin receptor blockade to PAPPA enzymatic inhibition. This fundamental mechanism change allows achieving the same therapeutic effect (cyst growth reduction) through a different biochemical pathway that avoids the harmful liver effects associated with tolvaptan
2Productivity
If PAPPA binding proteins inhibit cleavage of IGFBP-2, -4 and -5, then kidney cyst growth is reduced, but non-specific binding and self-association may increase
Solution Approach 1:
The patent applies local quality by designing antibodies with optimized binding interfaces that specifically recognize particular epitopes on PAPPA. The variable regions are engineered to have high affinity and specificity for PAPPA while minimizing interactions with other proteins, achieving selective inhibition of PAPPA-mediated IGFBP cleavage without excessive non-specific binding
Solution Approach 2:
The patent employs composite antibody structures combining optimized variable regions for PAPPA binding with engineered constant regions that minimize self-association. The composite design integrates multiple functional elements: high-affinity binding domains, reduced aggregation propensity, and optimized pharmacokinetic properties, creating an antibody with superior overall performance
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 PAPPA binding proteins demonstrate superior activity in inhibiting kidney cyst growth with lower toxicity and improved manufacturability, providing a safer and more effective treatment option for ADPKD.
Implementation Method 1
PAPPA binding proteins which neutralize the PAPPA-mediated cleavage of IGFBP-2, IGFBP-4 and IGFBP-5 proteins
Data Source
AI summary
The present disclosure relates to antigen binding proteins. More particularly the present disclosure relates to pregnancy associated plasma protein-A (PAPPA) binding proteins, even more particularly PAPPA binding proteins that inhibit cleavage of insulin like growth factor binding protein-2 (IGFBP-2), insulin like growth factor binding protein-4 (IGFBP-4) and insulin like growth factor binding protein-5 (IGFBP-5). The present disclosure further relates to the use of said binding proteins in medicine.