FSHR–CD3 Bispecific Binding Molecules for Chemoresistant Ovarian Cancer
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Solution Overview
Problem
Current treatments for ovarian cancer, particularly high-grade serous ovarian cancer and ovarian carcinosarcoma, are limited by chemoresistance and the lack of effective immune therapies targeting tumor cells while sparing normal tissues, necessitating the development of immune therapeutics that engage additional effector components of the immune system.
Innovation Solution
Development of bispecific binding molecules that target both CD3, a T cell receptor, and FSHR, a tumor-specific antigen, to enhance immune response and direct T cells to ovarian cancer cells, using nucleic acid molecules encoding these molecules for administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If surgery and chemotherapy are used as primary treatments for ovarian cancer, then tumor cells can be removed or suppressed, but patients develop chemoresistance and disease recurrence within a few years
Solution Approach 1:
The patent introduces bispecific binding molecules as intermediary agents that mediate between T cells and tumor cells. These molecules simultaneously bind to CD3 on T cells and FSHR on tumor cells, creating an immunological bridge that enables T cell-mediated cytotoxicity against ovarian cancer cells, thereby overcoming chemoresistance and extending disease-free survival without relying solely on chemotherapy
Solution Approach 2:
The patent replaces the mechanical/chemical mechanism of chemotherapy with an immunological mechanism. Instead of using cytotoxic chemicals that directly kill tumor cells (leading to resistance), the therapy uses bispecific molecules to activate the immune system's T cells to recognize and destroy tumor cells, providing a more durable and adaptable response that reduces recurrence
2Reliability
If immune checkpoint inhibitors are used for ovarian cancer treatment, then immune response can be stimulated, but extremely aggressive tumors such as high-grade serous ovarian cancer and ovarian carcinosarcoma respond poorly and are termed as Immunologically cold Tumors
Solution Approach 1:
The patent uses bisspecific binding molecules as intermediary agents that actively bridge the gap between the immune system and cold tumors. By simultaneously engaging T cells (via CD3 binding) and tumor cells (via FSHR binding), these molecules force an immunological interaction in tumors that would otherwise be inaccessible to T cells, thereby converting immunologically cold tumors into immunologically hot tumors with sustained T cell-mediated response
Solution Approach 2:
The patent extracts the FSHR target from the tumor cell surface and presents it to T cells through the bispecific molecule. This extraction allows T cells to directly engage with tumor-specific antigens without requiring the tumor to have inherent immunogenicity or热度, thereby overcoming the cold tumor barrier and enabling effective immune response in aggressive ovarian cancer subtypes
3Measurement precision
If CAR therapies are developed to target tumor cells, then specific tumor cell targeting is achieved, but the challenge is to find targets with specific expression confined to the surface of tumor cells but not on target off tumor tissues
Solution Approach 1:
The patent uses FSHR as an intermediary target that provides tumor-specificity. By designing bisspecific molecules that bind to FSHR on tumor cells and CD3 on T cells, the system achieves specific tumor targeting through a target (FSHR) that is selectively expressed on tumor cells rather than normal tissues, thereby simplifying the target selection process while maintaining high specificity
Solution Approach 2:
The patent changes the targeting approach from direct T cell engagement (requiring highly specific tumor markers) to FSHR-mediated engagement. This parameter change allows the use of FSHR, which has well-characterized selective expression in ovarian granulosa cells and 50-70% of serous ovarian carcinoma cases, thereby reducing target selection complexity while achieving effective tumor-specific targeting
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 bispecific binding molecules effectively enhance the immune response against ovarian cancer cells, potentially overcoming chemoresistance and improving treatment outcomes by specifically targeting tumor cells while minimizing off-target effects.
Implementation Method 1
a first binding domain that specifically binds to follicle stimulating hormone receptor (FSHR) and a second binding domain that specifically binds to a T cell specific receptor
Data Source
AI summary
The present invention provides bispecific binding molecules targeting CD3 and FSHR having increased expression and stability, and nucleic acid molecules encoding the same, and methods for treating or preventing a disease or disorder using the same.