Multispecific Polypeptide Antagonists for Dual TGF-beta and Activin Inhibition
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Solution Overview
Problem
Current treatments for various complex diseases, such as cancer and fibrosis, are limited by the inability to effectively inhibit both TGF-β and Activin signaling pathways simultaneously, which are often elevated and contribute to disease progression.
Innovation Solution
Development of novel multispecific polypeptide antagonist molecules that simultaneously neutralize Activin and TGF-β signaling by combining antigen-binding molecules specific to Activin and TGF-β ligands, including antibodies and their fragments, to inhibit both pathways concurrently.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single-specific antagonists are used to inhibit either TGF-β or Activin signaling, then one pathway is effectively blocked, but the other pathway remains active and continues to drive disease progression
Solution Approach 1:
The patent combines two separate antigen-binding molecules (one specific for TGF-β and one specific for Activin) into a single multispecific polypeptide antagonist. This merging allows the molecule to simultaneously bind and inhibit both TGF-β and Activin ligands, resolving the contradiction by providing dual pathway inhibition in one agent rather than requiring separate treatments for each pathway
Solution Approach 2:
The multispecific polypeptide antagonist is designed with multiple binding specificities, enabling a single molecule to perform multiple functions: blocking TGF-β signaling through TGFβRII/RIIB receptors and blocking Activin signaling through ActRIIA/ActRIIB receptors. This multi-functionality directly addresses the limitation of single-specific antagonists by providing broad pathway coverage
2Reliability
If multiple separate antagonist molecules are administered to block both TGF-β and Activin pathways, then both pathways are inhibited, but treatment complexity and potential off-target effects increase
Solution Approach 1:
Instead of administering multiple separate antagonist molecules, the patent merges the functionality of TGF-β-specific and Activin-specific antagonists into one multispecific polypeptide. This consolidation reduces treatment complexity from multiple agents to a single molecule while maintaining complete blockade of both signaling pathways
Solution Approach 2:
The single multispecific antagonist molecule is engineered to universally target both TGF-β and Activin pathways, replacing the need for multiple specialized agents. This universal approach simplifies the treatment regimen while ensuring comprehensive pathway inhibition
Data Source
AI summary
This invention disclosure describes novel polypeptide antagonists capable of neutralizing multiple members of TGF-β family in a selective manner. Specifically, the multispecific polypeptide antagonists disclosed herein comprise at least one Activin-binding domain and at least one TGF-β-binding domain and therefore, are capable of neutralizing TGF-β and Activin as well as Activin-related ligands in parallel. Moreover, this invention disclosure also discloses bifunctional multispecific polypeptide antagonists designed to inhibit Activin, TGF-β and T-Cell immune checkpoint (i.e., PD1, PDL1 or CTLA4) in a simultaneous manner. Specifically, the bifunctional multispecific antagonists disclosed herein comprise at least one Activin-binding domain, at least one TGF-β-binding domain and at least one PD1-, PDL1- or CTLA4-binding domain. Also provided are pharmaceutical compositions of such multispecific or bifunctional multispecific polypeptide antagonists and their therapeutic uses for treating certain disease conditions, which involve overexpression of both TGF-β and Activin, such as fibrosis and cancer.