uPAR Binding Molecules for Senescent Cell Elimination
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Solution Overview
Problem
Current therapies often fail to effectively target senescent cells, which can contribute to malignancies and fibrotic diseases, and there is a need for more effective treatments for cancers and fibrotic diseases, particularly those involving high urokinase-type plasminogen activator receptor (uPAR) expression.
Innovation Solution
Development of antigen binding molecules, such as single domain antibodies or bi-specific T cell engagers, with high affinity for uPAR, which can be administered to reduce the population of uPAR-expressing cells, either alone or linked to cytotoxic payloads in an antibody drug conjugate, to treat cancers and fibrotic diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used to target senescent cells, then treatment is provided, but the therapies fail to effectively target senescent cells which contribute to malignancies and fibrotic diseases
Solution Approach 1:
The patent develops antigen binding molecules with specifically optimized binding affinity parameters for uPAR, achieving KD values in the low nanomolar range. This parameter optimization enables effective targeting of senescent cells that express uPAR, resolving the inadequacy of current therapies. The molecules are engineered with specific amino acid sequences that enhance binding strength and selectivity for uPAR-expressing cells.
Solution Approach 2:
The patent introduces antigen binding molecules (such as single-domain antibodies and bi-specific T cell engagers) as intermediary agents that specifically bind to uPAR on senescent cells. These intermediaries bridge the gap between the immune system and target cells, enabling selective recognition and elimination of senescent cells that contribute to malignancies and fibrotic diseases, thereby resolving the failure of current direct therapies.
2Object-affected harmful factors
If high uPAR expression is present in cancers, then tumor progression occurs, but this also provides a specific target for therapy
Solution Approach 1:
The patent converts the harmful overexpression of uPAR in cancer cells into a beneficial therapeutic target. By developing high-affinity antigen binding molecules that specifically recognize uPAR, the invention transforms the cancer-promoting characteristic (high uPAR expression) into a vulnerability that can be exploited for selective therapy. The molecules selectively bind to and eliminate uPAR-expressing cancer cells while sparing normal cells with lower uPAR expression.
3Reliability
If senescent cells are not targeted by current therapies, then they persist and contribute to malignancies, but developing new targeted therapies increases treatment complexity
Solution Approach 1:
The patent extracts and isolates the specific antigen-binding function required to target senescent cells, implementing it through single-domain antibodies and bi-specific T cell engagers. These streamlined molecular structures perform the essential targeting function without the complexity of full-length antibodies or conventional chemotherapy regimens. The extracted binding domains can be produced more simply and administered with reduced complexity while maintaining effective senescent cell elimination.
Data Source
AI summary
Provided herein are single-domain antigen binding molecules able to bind uPAR. Also provided herein are methods of treating cancer, fibrotic disease, or diseases related to senescent cell phenotypes in which uPAR is expressed.