Anti-TGFbetaRII Variable Domain Binding Affinity
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Solution Overview
Problem
Current therapies lack effective solutions for dysregulated TGFbeta signaling, which contributes to various pathologies such as pulmonary fibrosis, rheumatoid arthritis, and ocular disorders, due to the need for specific compounds that can block or disrupt TGFbeta signaling, particularly by binding to TGFbeta receptor II.
Innovation Solution
Development of an anti-TGFbetaRII immunoglobulin single variable domain with a specific amino acid sequence that binds to human, mouse, and cyno TGFbetaRII with high affinity, neutralizing TGFbeta activity or inhibiting its binding to TGFbetaRII, potentially linked to an antibody Fc region for enhanced stability and delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies are used for dysregulated TGFbeta signaling, then treatment options are limited, but they cannot effectively block or disrupt TGFbeta signaling
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the immunoglobulin single variable domain to achieve high binding affinity (KD of about 10pM or less) to TGFbetaRII. This specific sequence optimization enables the therapeutic agent to effectively block TGFbeta signaling, resolving the contradiction between therapy effectiveness and ability to disrupt signaling.
2Reliability
If high affinity binding to TGFbetaRII is achieved, then TGFbeta signaling is effectively blocked, but the complexity of developing specific compounds increases
Solution Approach 1:
The patent extracts and isolates the essential binding domain (single variable domain) from the complete antibody structure. This extraction achieves high binding affinity to TGFbetaRII while simplifying the overall molecular structure, thereby reducing the complexity of compound development and production compared to full-length antibodies.
Solution Approach 2:
The patent uses immunoglobulin single variable domains as simplified copies or fragments of full antibodies that retain the essential binding function. This copying approach maintains high binding affinity while reducing structural complexity, making the therapeutic agent easier to develop and produce.
3Adaptability or versatility
If immunoglobulin single variable domain is used, then TGFbeta signaling is specifically inhibited, but the stability and delivery may be compromised compared to full antibodies
Solution Approach 1:
The patent links the immunoglobulin single variable domain to an antibody Fc region, creating a fusion protein that combines the specific binding capability of the variable domain with the stability and effector functions of the Fc region. This intermediary structure resolves the contradiction by maintaining specificity while enhancing stability and delivery properties.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The anti-TGFbetaRII immunoglobulin single variable domain effectively inhibits TGFbeta signaling, providing a therapeutic approach for conditions like pulmonary fibrosis, rheumatoid arthritis, and ocular disorders by specifically targeting TGFbeta receptor II, offering a potential treatment for fibrosis and scarring reduction.
Implementation Method 1
binds to human TGFbetaRII with an equilibrium dissociation constant (KD) of about 10pM or less as measured by surface plasmon resonance
Implementation Method 2
as measured by surface plasmon resonance
Data Source
AI summary
The disclosure provides an anti -TGFbetaRII immunoglobulin single variable domain. Suitably, an anti -TGFbetaRII immunoglobulin single variable domain in accordance with the disclosure is one having an amino acid sequence as set forth in any one of SEQ ID NO: 1-38, 204, 206, 208, 214, 234, 236, 238, 240, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289 or 291 having up to 5 amino acid substitutions, deletions or additions. The disclosure further provides a polypeptide and pharmaceutical composition for treating a disease associated with TGFbeta signalling and suitably a disease selected from the group of: tissue fibrosis, such as pulmonary fibrosis, including idiopathic pulmonary fibrosis; liver fibrosis, including cirrhosis and chronic hepatitis; rheumatoid arthritis; ocular disorders; fibrosis of the skin, including keloid of skin; Dupuytren's Contracture; kidney fibrosis such as nephritis and nephrosclerosis; wound healing; scarring reduction; and a vascular condition, such as restenosis.