Hybrid ActRIIB Ligand Traps With Reduced BMP9 Binding
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Solution Overview
Problem
Existing therapeutics for muscle wasting and bone diseases associated with chronic, neurological, genetic, inflammatory, fibrotic, or infectious pathologies are either ineffective or pose safety concerns, such as adverse events like nose and gum bleeding.
Innovation Solution
Development of hybrid ActRIIB ligand trap proteins that attenuate muscle wasting and bone loss by administering a therapeutically effective amount of a hybrid ActRIIB ligand trap, which binds myostatin and activin A while reducing affinity for BMP9 to minimize adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ActRIIB-Fc fusion proteins are used to treat muscle wasting and bone diseases, then muscle growth and bone anabolism are promoted, but adverse events such as nose and gum bleeding occur due to BMP9 binding
Solution Approach 1:
The patent applies local quality by modifying specific amino acid residues at the BMP9 binding interface of ActRIIB while preserving the overall receptor structure. This allows selective alteration of BMP9 binding affinity without affecting myostatin and activin A binding capabilities, thereby achieving localized functional differentiation to eliminate adverse effects while maintaining therapeutic benefits
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences at the BMP9 binding interface (such as residues in the type II receptor binding pocket) to modulate binding affinity. Through iterative optimization of these molecular parameters, the invention achieves reduced BMP9 binding while preserving binding to myostatin and activin A, thus resolving the contradiction between therapeutic efficacy and safety
2Productivity
If wild-type ActRIIB-Fc is used to block BMP9 signaling, then muscle growth is enhanced, but vascular homeostasis is disrupted leading to bleeding side effects
Solution Approach 1:
The patent applies segmentation by dividing the ligand binding function into distinct segments: one segment (ActRIIB) that binds myostatin and activin A to promote muscle growth, and another segment (modified binding interface) that has reduced affinity for BMP9 to avoid vascular side effects. This functional segmentation allows independent optimization of each binding interaction
Solution Approach 2:
The patent uses engineered ActRIIB variants as intermediaries that selectively mediate the effects of myostatin and activin A while acting as a filter to exclude BMP9. This intermediary approach allows the therapeutic agent to transmit beneficial signals while blocking harmful signals, resolving the contradiction between productivity and reliability
Data Source
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AI summary
The present disclosure describes novel hybrid soluble ActRIIB-ECD polypeptides which fully retain binding affinity for myostatin and activin A but demonstrate significantly reduced binding to BMPs, especially BMP-9. The novel compositions described herein can be used to prepare novel hybrid ActRIIB ligand trap proteins, which can be used for modulating the growth of muscle, bone, cartilage, fat, fibroblast, blood and neuronal tissue to counteract muscle wasting, bone loss, anemia, inflammation and fibrosis in a therapeutically meaningful manner. Because these novel next-generation myostatin/activin inhibitors are safer and more effective molecules than the currently available myostatin inhibitors, they are useful in a wide variety of clinical indications.