Hybrid ActRIIB Ligand Trap Proteins for Muscle and Bone Therapy
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Solution Overview
Problem
Current therapeutics for muscle wasting and bone diseases associated with chronic, neurological, genetic, inflammatory, fibrotic, or infectious pathologies face safety concerns and efficacy limitations, particularly due to adverse effects like nose and gum bleeding caused by strong BMP9 neutralization.
Innovation Solution
Development of a hybrid ActRIIB ligand trap protein with specific amino acid substitutions that reduce BMP9 binding affinity while maintaining myostatin and activin A neutralization, formulated with a pharmaceutically acceptable carrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If wild-type ActRIIB-Fc is used to treat muscle wasting and bone disease, then muscle growth and bone anabolism are significantly improved, but bleeding side effects (nose and gum bleeding) occur due to strong BMP9 neutralization
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions (F58L/E70Q, F58L/E70R, F58L/E70S, or F58L/E70T) at particular positions in the ActRIIB-Fc protein sequence. These localized changes selectively reduce BMP9 binding affinity while preserving myostatin and activin A neutralization capabilities, thereby reducing bleeding side effects without compromising muscle growth and bone anabolism benefits
Solution Approach 2:
The patent changes the biochemical parameters of the ActRIIB-Fc protein by substituting specific amino acid residues. This parameter change reduces the binding affinity for BMP9 (thereby reducing bleeding side effects) while maintaining adequate binding affinity for myostatin and activin A (preserving therapeutic efficacy for muscle and bone conditions)
2Reliability
If ActRIIB-Fc is used to neutralize myostatin and activin A, then muscle wasting is effectively treated, but BMP9 signaling is also blocked causing vascular side effects
Solution Approach 1:
The patent introduces localized amino acid substitutions at positions 58 and 70 of the ActRIIB-ECD sequence. These specific local changes create a differential binding profile where BMP9 interaction is reduced while myostatin and activin A binding is preserved, thereby treating muscle wasting effectively without causing vascular side effects
Solution Approach 2:
The modified ActRIIB-Fc protein acts as an intermediary that selectively intercepts myostatin and activin A signaling pathways while allowing BMP9 signaling to proceed. The amino acid substitutions create a filtering effect where harmful BMP9 blockade is prevented while beneficial myostatin/activin A neutralization is maintained
Data Source
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AI summary
The present disclosure describes novel hybrid soluble ActRIIB-ECD polypeptides. The present disclosure provides methods for treating or preventing muscle wasting, bone disease, a metabolic, fibrosis, an autoimmune/inflammatory, cardiovascular disease, cancer or cancer, chronic kidney disease (CKD), arthritis, anorexia, liver disease, organ or tissue transplant rejection, anemia, pain, and/or aging in a subject in need thereof. Further, the present disclosure provides methods of inducing stem cell growth for tissue repair or organ regeneration in a subject. The aforementioned methods comprising administering to the subject a therapeutically effective amount of a hybrid ActRIIB ligand trap polypeptide. The present disclosure also provides pharmaceutical compositions comprising hybrid ActRIIB ligand trap polypeptides.