Extracellular ActRIIB Variants for Selective TGF-β Ligand Modulation

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

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 current treatments are limited or ineffective.

Innovation Solution

Polypeptides comprising extracellular activin receptor type IIB (ActRIIB) variants, which can be 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, and affect signaling pathways like activin and BMP9, addressing the underlying conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments (corticosteroids, splenectomy, platelet transfusion) are used for thrombocytopenia, then immediate symptom relief may be achieved, but long-term effectiveness is limited and carries significant risks

Engineering Contradiction:

Improvelong-term treatment effectivenessVSAvoidtreatment risks and side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses activin receptor type IIB (ActRIIB) as an intermediary molecule that selectively binds to and neutralizes TGF-beta superfamily ligands (activin A, activin B, myostatin) without binding to BMP9. This intermediary approach allows specific modulation of pathological signaling pathways while preserving essential BMP9-mediated hematopoietic functions, thereby achieving long-term effectiveness without the harmful effects of current treatments

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention modifies the binding parameters of ActRIIB by introducing specific amino acid substitutions (e.g., E75K, Q69T, E70D) that reduce BMP9 binding affinity while maintaining or enhancing binding to activin A, activin B, and myostatin. This parameter change enables selective inhibition of harmful pathways while preserving beneficial BMP9 signaling for blood cell production

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If growth factors are used to stimulate white blood cell production in neutropenia, then neutrophil levels may increase, but treatment options remain limited and effectiveness varies

Engineering Contradiction:

Improveneutrophil countVSAvoidtreatment versatility

Core Design Contradiction:

Quantity of substanceVSAdaptability or versatility

Solution Approach 1:

The ActRIIB polypeptide exhibits multi-functionality by simultaneously addressing multiple hematopoietic parameters - it can increase neutrophil counts in neutropenia, platelet counts in thrombocytopenia, and red blood cell production in anemia, all through the same mechanism of blocking TGF-beta superfamily ligand binding. This universal approach overcomes the limitation of condition-specific treatments

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If bone marrow transplant or aggressive therapies are used for myelofibrosis, then disease progression may be halted, but treatment risks and complexity increase significantly

Engineering Contradiction:

Improvedisease progression controlVSAvoidtreatment complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent extracts and isolates the specific pathological mechanism in myelofibrosis - excessive TGF-beta superfamily ligand binding to ActRIIB - and selectively targets only this pathway using engineered ActRIIB polypeptides. This extraction approach allows treatment of the underlying cause without the complexity and risks of bone marrow transplant or aggressive chemotherapies

Inventive Principle:

Principle #2Taking out (Extraction)

4Quantity of substance

If erythropoiesis stimulating agents are used for MDS-associated anemia, then red blood cell production may improve, but these agents are not approved for such treatment and safety concerns exist

Engineering Contradiction:

Improvered blood cell productionVSAvoidtreatment approval and safety

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The invention converts the harmful effect of TGF-beta superfamily ligands (which inhibit erythropoiesis in MDS) into a beneficial therapeutic target. By blocking these ligands with engineered ActRIIB polypeptides, the patent indirectly stimulates red blood cell production through a safer, more targeted mechanism than direct ESA use, avoiding the safety concerns and lack of approval for ESA in MDS

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS12440539B2Methods of using activin receptor type IIB variants

Publication Date: 2025.10.14 KEROS THERAPEUTICS INC

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.