ActRIIB Variant Fc Polypeptides With Reduced BMP9 Binding
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Solution Overview
Problem
There is a need for novel and effective treatments for conditions such as thrombocytopenia, neutropenia, myelofibrosis, myelodysplastic syndromes, osteogenesis imperfecta, neuromuscular diseases, and metabolic diseases, as existing treatments are limited or ineffective.
Innovation Solution
Polypeptides comprising extracellular activin receptor type IIB (ActRIIB) variants, optionally fused to an Fc domain monomer, are used to increase lean mass, muscle mass, bone mass, red blood cell levels, platelet levels, neutrophil levels, or reduce body weight, by modulating signaling pathways like activin and BMP9.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used for conditions like thrombocytopenia, neutropenia, myelofibrosis, and other hematologic disorders, then current standard therapies are applied, but treatment effectiveness is limited and adverse effects occur
Solution Approach 1:
The patent modifies the activin receptor type IIB protein by introducing specific amino acid substitutions (e.g., E75K, Q69T, E70D) to alter its binding properties. These parameter changes in the protein structure enable selective binding to activin and myostatin while reducing binding to BMP9, thereby improving therapeutic effectiveness and reducing adverse effects associated with existing treatments
Solution Approach 2:
The invention introduces specific local modifications at particular amino acid positions within the activin receptor type IIB protein sequence. These localized changes (such as substitutions at positions 69, 70, 75, and others) create a receptor variant with enhanced specificity for certain ligands, allowing targeted therapeutic action while sparing other pathways from unwanted activation or inhibition
2Reliability
If activin receptor type IIB is used to treat conditions, then therapeutic benefits are achieved, but BMP9 binding may cause unwanted effects
Solution Approach 1:
The patent employs parameter changes by substituting specific amino acids (such as Q69T, E70D, Q69D, E70T) in the activin receptor type IIB to fundamentally alter its ligand binding profile. These modifications reduce or eliminate BMP9 binding while preserving or enhancing binding to activin and myostatin, thereby achieving therapeutic benefits without the harmful effects of unwanted BMP9 interactions
Solution Approach 2:
The invention converts the potential harm of BMP9 binding into a benefit by designing receptor variants that specifically exclude BMP9 while maintaining affinity for therapeutic targets. The amino acid substitutions create a binding pocket configuration that is selective for activin and myostatin, effectively using the receptor's natural binding capability to achieve specificity that eliminates harmful off-target effects
Data Source
AI summary
The invention features polypeptides that include an extracellular ActRIIB variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRIIB variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions containing said polypeptides and methods of using the polypeptides to treat diseases and conditions including neuromuscular diseases, osteogenesis imperfecta, myelofibrosis, thrombocytopenia, neutropenia, and metabolic disease.