Fc-Beta2GPI Constructs for Tumor Vasculature Targeting
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Solution Overview
Problem
Current cancer treatments face challenges in achieving a 'total cell kill' due to tumor resistance, particularly in solid tumors, as chemotherapeutic agents struggle to reach all cells and solid tumors are impermeable to macromolecular agents, leading to limited effectiveness and toxic side effects. Additionally, there is a need for improved therapeutic and vascular targeting agents that do not rely on antibodies for targeting, to enhance host effector functions and treat viral infections.
Innovation Solution
Development of new phosphatidylserine binding constructs, such as receptorbodies and betabodies, which comprise a phosphatidylserine binding protein or polypeptide attached to an antibody Fc region, allowing for specific targeting and destruction of phosphatidylserine-exposed disease sites, and conjugation with diagnostic and therapeutic agents for enhanced delivery and treatment efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemotherapeutic agents are used to treat solid tumors, then some tumor cells are killed, but the agents struggle to reach all cells and toxic side effects occur
Solution Approach 1:
The invention segments the treatment approach by targeting tumor vasculature specifically rather than treating all cells systemically. The Fc-β2GPI constructs localize to phosphatidylserine-exposed endothelial cells in tumor blood vessels, delivering the therapeutic effect locally to the vasculature while sparing healthy tissues, thereby reducing toxic side effects while maintaining treatment reliability
Solution Approach 2:
The invention uses Fc-β2GPI constructs as intermediary agents that bind to phosphatidylserine on tumor vasculature and deliver therapeutic payloads (toxins, coagulation factors, or immunostimulants) to the target site. This intermediary approach enables selective delivery to tumor blood vessels, improving treatment effectiveness while minimizing systemic toxicity
2Measurement precision
If macromolecular agents such as antibodies are used for tumor targeting, then specific targeting is achieved, but solid tumors are impermeable to these agents
Solution Approach 1:
The invention applies partial action by targeting only the tumor vasculature (endothelial cells) rather than attempting to penetrate and treat the entire solid tumor mass. The Fc-β2GPI constructs bind to phosphatidylserine on the luminal surface of tumor blood vessels, achieving sufficient therapeutic effect by disrupting the blood supply without requiring deep tumor penetration
Solution Approach 2:
The invention uses Fc-β2GPI constructs that replicate the phosphatidylserine-binding function of natural proteins like annexin V and β2-glycoprotein I, but with enhanced properties through fusion to the antibody Fc region. This copying approach allows the construct to achieve both specificity and improved pharmacokinetics without the size limitations of full-length antibodies
3Measurement precision
If conventional antibody-based immunotoxins are used, then tumor cells are targeted, but antigen-negative or antigen-deficient cells can survive and repopulate
Solution Approach 1:
The invention uses phosphatidylserine as a universal target marker that is exposed on all tumor vasculature endothelial cells regardless of their antigen expression status. Since phosphatidylserine exposure is a common feature of activated and proliferating endothelial cells in tumors, the Fc-β2GPI constructs can target all tumor blood vessels uniformly, preventing antigen-negative cell survival and achieving more complete eradication
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
These constructs effectively bind phosphatidylserine targets, enhance host effector functions, and deliver therapeutic agents to specific sites, improving cancer treatment and viral infection management by increasing the effectiveness of treatments while minimizing side effects and overcoming tumor resistance.
Implementation Method 1
The constructs comprise a phosphatidylserine binding protein or polypeptide attached to an antibody Fc region, allowing for specific targeting and destruction of phosphatidylserine-exposed disease sites
Implementation Method 2
These constructs effectively bind phosphatidylserine targets, enhance host effector functions, and deliver therapeutic agents to specific sites
Implementation Method 3
The new constructs effectively bind phosphatidylserine disease targets and enhancing their destruction, and can also deliver therapeutic agents to specific sites
Data Source
AI summary
Disclosed are new phosphatidylserine binding constructs with surprising combinations of properties, and a range of diagnostic and therapeutic conjugates thereof. The new constructs effectively bind phosphatidylserine targets in disease and enhance their destruction, and can also specifically deliver attached imaging or therapeutic agents to the disease site. Also disclosed are methods of using the new construct compositions, therapeutic conjugates and combinations thereof in tumor vasculature targeting, cancer diagnosis and treatment, and for treating viral infections and other diseases.