Humanized Antibodies Targeting Tissue Factor Without Coagulation Inhibition
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Solution Overview
Problem
Current cancer treatments using antibodies that bind to the TF-FVIIa interaction site can inhibit blood coagulation, leading to compromised bleeding control in patients, and there is a need for improved cancer therapies that specifically target human tissue factor without affecting normal tissue factor-mediated blood coagulation.
Innovation Solution
Development of humanized antibodies and antibody-drug conjugates that specifically bind to human tissue factor with high affinity, maintaining normal blood coagulation function by using specific heavy and light chain variable regions with at least 90% sequence identity to specified sequences, and conjugating these antibodies with cytotoxic agents like maytansine or auristatin for targeted cancer therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibodies that bind to the TF-FVIIa interaction site are used for cancer therapy, then tumor cells overexpressing tissue factor are targeted, but normal tissue factor-mediated blood coagulation is inhibited leading to bleeding complications
Solution Approach 1:
The patent applies local quality by creating antibodies with species-specific binding characteristics. The humanized antibodies are engineered to recognize and bind exclusively to human tissue factor (hTF) while leaving mouse/rat TF (mTF/rTF) unaffected. This is achieved through humanizing the variable regions (VH and VL domains) of the antibody while retaining the constant regions, thereby conferring species-specificity. The antibody binds to the hTF-FVIIa interaction site on human tumor cells, delivering cytotoxic payloads selectively, while mouse/rat coagulation systems remain intact and functional.
Solution Approach 2:
The patent employs parameter changes by modifying the antibody structure from fully murine to humanized format. This structural parameter change alters the binding specificity parameter, enabling the antibody to recognize human TF epitopes while not cross-reacting with mouse/rat TF. The humanization process involves replacing murine variable region sequences with human framework sequences while preserving the complementarity-determining regions (CDRs) that confer antigen binding specificity, thereby changing the immunological recognition parameters.
2Productivity
If large quantities of antibodies are used to target tissue factor on tumor cells, then cancer therapy efficacy is improved, but bleeding control in patients is compromised
Solution Approach 1:
The patent applies local quality by creating antibodies with species-specific binding characteristics. The humanized antibodies are engineered to recognize and bind exclusively to human tissue factor (hTF) while leaving mouse/rat TF (mTF/rTF) unaffected. This is achieved through humanizing the variable regions (VH and VL domains) of the antibody while retaining the constant regions, thereby conferring species-specificity. The antibody binds to the hTF-FVIIa interaction site on human tumor cells, delivering cytotoxic payloads selectively, while mouse/rat coagulation systems remain intact and functional.
Solution Approach 2:
The patent employs parameter changes by modifying the antibody structure from fully murine to humanized format. This structural parameter change alters the binding specificity parameter, enabling the antibody to recognize human TF epitopes while not cross-reacting with mouse/rat TF. The humanization process involves replacing murine variable region sequences with human framework sequences while preserving the complementarity-determining regions (CDRs) that confer antigen binding specificity, thereby changing the immunological recognition parameters.
3Reliability
If antibodies binding to TF-FVIIa interaction site are used, then tumor growth and metastasis are targeted, but normal blood coagulation function is inhibited
Solution Approach 1:
The patent applies local quality by creating antibodies with species-specific binding characteristics. The humanized antibodies are engineered to recognize and bind exclusively to human tissue factor (hTF) while leaving mouse/rat TF (mTF/rTF) unaffected. This is achieved through humanizing the variable regions (VH and VL domains) of the antibody while retaining the constant regions, thereby conferring species-specificity. The antibody binds to the hTF-FVIIa interaction site on human tumor cells, delivering cytotoxic payloads selectively, while mouse/rat coagulation systems remain intact and functional.
Solution Approach 2:
The patent employs parameter changes by modifying the antibody structure from fully murine to humanized format. This structural parameter change alters the binding specificity parameter, enabling the antibody to recognize human TF epitopes while not cross-reacting with mouse/rat TF. The humanization process involves replacing murine variable region sequences with human framework sequences while preserving the complementarity-determining regions (CDRs) that confer antigen binding specificity, thereby changing the immunological recognition parameters.
Data Source
AI summary
The present disclosure provides humanized antibodies and antibody-drug conjugates that specifically bind to human tissue factor, and which do not inhibit tissue factor mediated blood coagulation compared to a normal plasma control. Further described are methods of making and methods of using the disclosed humanized antibodies and antibody-drug conjugates in the treatment of cancer.