Internalizing Binding Molecules for Fibrosis Targeting
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Solution Overview
Problem
Current treatments for fibrosis lack effective and safe therapeutic options, particularly for advanced stages where organ function is compromised, and existing molecules like Rho-kinase inhibitors and JAK-2 kinase inhibitors have cumbersome safety profiles.
Innovation Solution
Development of binding molecules comprising single variable antibody domains that specifically target transmembrane receptors over-expressed on fibrogenic effector cells, such as PDGFRB and IGF2R, allowing for the selective delivery of therapeutic molecules like kinase inhibitors or cytotoxic substances to reduce fibrotic activity and attenuate the fibrotic process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional kinase inhibitors (Rho-kinase inhibitors, JAK-2 kinase inhibitors) are used to treat fibrosis, then therapeutic effect is achieved, but safety profile deteriorates with cumbersome side effects
Solution Approach 1:
The binding molecule employs single variable antibody domains that specifically recognize and bind to transmembrane receptors (PDGFRB, IGF2R) that are over-expressed on fibrogenic effector cells. This localized targeting delivers the therapeutic kinase inhibitor exclusively to the pathological cells, achieving effective inhibition of fibrosis while avoiding systemic exposure and reducing side effects
Solution Approach 2:
The binding molecule acts as an intermediary carrier that combines the specificity of antibody domains with the therapeutic action of kinase inhibitors. The antibody domains serve as targeting moieties that guide the therapeutic agent to the intended cellular destination, enabling precise delivery while minimizing off-target effects
2Reliability
If systemic treatment is applied to treat fibrosis, then therapeutic coverage is improved, but off-target toxicity increases
Solution Approach 1:
The binding molecule achieves selective accumulation in fibrogenic effector cells through specific binding to over-expressed transmembrane receptors. This localized delivery ensures therapeutic action is concentrated where needed (in fibrotic tissue) while normal tissues receive minimal to no exposure, thereby eliminating the trade-off between coverage and toxicity
3Reliability
If broad-spectrum anti-fibrotic treatment is used, then overall fibrotic process is addressed, but specificity to fibrogenic effector cells decreases leading to increased toxicity
Solution Approach 1:
The single variable antibody domains are engineered to recognize specific epitopes on transmembrane receptors that are differentially expressed on fibrogenic effector cells versus normal cells. This molecular-level specificity ensures that the therapeutic effect is restricted to the pathological cell population, achieving both broad anti-fibrotic coverage and high cell specificity simultaneously
Solution Approach 2:
The invention exploits the differential expression parameter of transmembrane receptors (PDGFRB, IGF2R) between fibrogenic effector cells and normal cells. By targeting receptors that are over-expressed specifically on activated fibrogenic cells, the binding molecule achieves selective accumulation and internalization only in the target cells, maintaining high specificity while delivering effective therapeutic doses
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 binding molecules effectively target and reduce the activity of fibrogenic effector cells, potentially reversing fibrosis by specifically delivering therapeutic agents, thereby reducing off-target toxicity and providing a safer treatment option for fibrotic conditions.
Implementation Method 1
binding molecules comprising single variable antibody domains that specifically target transmembrane receptors over-expressed on fibrogenic effector cells
Implementation Method 2
internalizing binding molecules for cell-specific targeted delivery of anti-fibrotic substances
Data Source
AI summary
The invention relates to the field of binding molecules comprising at least one single variable antibody domain, targeted at receptors present on fibrogenic effector cells, such as activated hepatic stellate cells in liver fibrosis, activated interstitial fibroblasts or vascular smooth muscle cells in lung fibrosis, activated mesangial- or interstitial fibroblasts in renal fibrosis, activated dermal fibroblasts in systemic sclerosis/scleroderma, activated fibroblasts in inflammatory bowel disease, or tumor-supporting stromal fibroblasts in sclerosing malignant tumors. More in particular, the invention relates to internalizing binding molecules for cell-specific targeted delivery of anti-fibrotic substances. The invention also relates to a binding molecule comprising at least two single variable antibody domains, each targeting a receptor on said fibrogenic effector cells. The invention further relates to nucleic acids encoding such binding molecules, a host cell for expression of such binding molecules and to methods for preparing such binding molecules. The invention further relates to pharmaceutical compositions that comprise such binding molecule and to uses of such binding molecules and/or compositions, in particular for prophylactic, therapeutic or diagnostic purposes.