ActRIIB ECD Variants for BMP-9-Sparing Ligand Neutralization

Solution Overview

Problem

Current therapeutics for TGFβ superfamily-associated disorders often disrupt BMP-9 signaling, leading to vascular complications, while failing to effectively neutralize other TGFβ superfamily ligands, thus necessitating a tailored approach to maximize therapeutic efficacy and minimize adverse effects.

Innovation Solution

Development of ActRIIB-ECD variants with specific amino acid substitutions that enhance binding to activin A, activin B, GDF-8, and GDF-11 while reducing binding to BMP-9, allowing for targeted neutralization of these ligands and maintaining BMP-9 signaling, thereby minimizing vascular disruption.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild type ActRIIB binds to BMP-9 to neutralize TGFβ superfamily ligands, then neutralization of activin A, activin B, GDF-8, and GDF-11 is achieved, but vascular homeostasis is disrupted leading to bleeding complications

Engineering Contradiction:

Improveneutralization efficacyVSAvoidvascular complications

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific amino acid substitutions (e.g., G27D, Q29Y, D30Q, K31Y, S38R, D57E, F58D, V75Q, F77D) at particular positions within the ActRIIB ectodomain to selectively modify ligand binding properties. These localized changes alter the binding interface to reduce BMP-9 affinity while preserving or enhancing binding to other TGFβ superfamily ligands, thereby achieving tailored ligand specificity that spares vascular homeostasis.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying amino acid residues at key binding positions to tune the binding affinity and specificity of ActRIIB for different ligands. Through iterative optimization of these molecular parameters, the invention achieves a binding profile where BMP-9 affinity is reduced by at least 2-fold compared to wild type, while maintaining or improving neutralization of activin A, activin B, GDF-8, and GDF-11.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If ActRIIB-ECD traps are used to neutralize TGFβ superfamily ligands, then therapeutic effects on pulmonary hypertension and fibrosis are achieved, but BMP-9 signaling is inhibited causing telangiectasias and epistaxis

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidbleeding events

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific amino acid substitutions (e.g., G27D, Q29Y, D30Q, K31Y, S38R, D57E, F58D, V75Q, F77D) at particular positions within the ActRIIB ectodomain to selectively modify ligand binding properties. These localized changes alter the binding interface to reduce BMP-9 affinity while preserving or enhancing binding to other TGFβ superfamily ligands, thereby achieving tailored ligand specificity that spares vascular homeostasis.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying amino acid residues at key binding positions to tune the binding affinity and specificity of ActRIIB for different ligands. Through iterative optimization of these molecular parameters, the invention achieves a binding profile where BMP-9 affinity is reduced by at least 2-fold compared to wild type, while maintaining or improving neutralization of activin A, activin B, GDF-8, and GDF-11.

Inventive Principle:

Principle #35Parameter changes

3Object-affected harmful factors

If ActRIIB-ECD variants with amino acid substitutions are developed to reduce BMP-9 binding, then vascular homeostasis is maintained, but ligand neutralization efficacy may be compromised

Engineering Contradiction:

Improvevascular disruptionVSAvoidligand neutralization

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent applies local quality by introducing specific amino acid substitutions (e.g., G27D, Q29Y, D30Q, K31Y, S38R, D57E, F58D, V75Q, F77D) at particular positions within the ActRIIB ectodomain to selectively modify ligand binding properties. These localized changes alter the binding interface to reduce BMP-9 affinity while preserving or enhancing binding to other TGFβ superfamily ligands, thereby achieving tailored ligand specificity that spares vascular homeostasis.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying amino acid residues at key binding positions to tune the binding affinity and specificity of ActRIIB for different ligands. Through iterative optimization of these molecular parameters, the invention achieves a binding profile where BMP-9 affinity is reduced by at least 2-fold compared to wild type, while maintaining or improving neutralization of activin A, activin B, GDF-8, and GDF-11.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12421296B2Activin receptor type IIB variants and uses thereof

Publication Date: 2025.09.23 GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 3) LIMITED

AI summary

There are provided polypeptides that include an Activin receptor type IIB (ActRIIB) ectodomain (ECD) variant. In some embodiments, a polypeptide of the disclosure includes an ActRIIB-ECD variant fused to an Fc domain moiety. The disclosure also provides pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions associated with TGFβ superfamily ligand signaling, such as pulmonary hypertension, fibrosis, muscle weakness and atrophy, metabolic disorders and/or cardiometabolic disease, bone damage, and/or low red blood cell levels (such as anemia).