TNF Trimer Antigen Binding Molecule Targeting Tenascin-C
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Solution Overview
Problem
Current 4-1BB agonists induce liver toxicity and uncontrollable side effects due to systemic administration, necessitating the development of effective 4-1BB agonists that target tumor cells without relying on Fc-receptor binding.
Innovation Solution
Design and production of TNF family ligand trimer-containing antigen binding molecules with specific binding to Tenascin-C (TnC), comprising two ectodomains connected by a peptide linker and one ectodomain linked by a disulfide bond, to target tumor cells effectively while minimizing Fc-receptor interaction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If 4-1BB agonists are administered systemically, then they can activate T-cells and produce anti-tumor effects, but they induce liver toxicity and uncontrollable side effects
Solution Approach 1:
The molecule is divided into distinct functional domains: a Tenascin-C binding domain (scFv) for targeted recognition, a linker region for structural flexibility, and a 4-1BBL ectodomain for immune activation. This segmentation allows the molecule to bind specifically to tumor cells via TnC while presenting 4-1BB ligand only at the tumor site, avoiding systemic toxicity
Solution Approach 2:
The Tenascin-C binding moiety acts as an intermediary that directs the 4-1BBL ligand specifically to tumor cells. By binding to TnC which is overexpressed in tumors, the molecule localizes its immunostimulatory effect to the tumor microenvironment rather than distributing systemically, thus preventing liver toxicity while maintaining anti-tumor efficacy
2Ease of operation
If Fc-receptor binding is utilized for 4-1BB agonist delivery, then systemic distribution and T-cell activation are achieved, but off-target effects and liver toxicity increase
Solution Approach 1:
The invention extracts the Fc portion from the antibody structure, using only the antigen-binding variable regions (scFv) fused to the 4-1BBL ligand. This removal of the Fc domain eliminates Fc-receptor interactions that cause off-target effects and liver toxicity, while preserving the targeted delivery capability through Tenascin-C binding
Solution Approach 2:
The molecule is designed to concentrate its immunostimulatory activity locally at the tumor site by binding to Tenascin-C, which is overexpressed in tumors. The 4-1BBL ligand is presented only where TnC is present, creating localized T-cell activation without systemic distribution, thereby avoiding off-target effects
3Duration of action of moving object
If traditional antibody structures are used for 4-1BB agonism, then Fc-receptor binding provides systemic distribution, but this causes liver toxicity
Solution Approach 1:
The invention uses a truncated antibody structure (scFv-based) without the long-lived Fc domain, creating a molecule that is cleared more rapidly from the system. This shorter half-life prevents accumulation in the liver and reduces toxicity, while the molecule remains effective at its target site due to high-affinity Tenascin-C binding
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 molecules provide stable and targeted 4-1BB agonism, enhancing cancer treatment efficiency and safety by specifically binding to tumor cells, reducing systemic toxicity.
Implementation Method 1
a first and a second polypeptide that are linked to each other by a disulfide bond
Data Source
AI summary
The invention relates to novel TNF family ligand trimer-containing antigen binding molecules comprising (a) at least one antigen binding moiety capable of specific binding to Tenascin-C (TnC) and (b) a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the antigen binding molecules are characterized in that the first polypeptide comprises two ectodomains of a TNF ligand family member or two fragments thereof that are connected to each other by a peptide linker and in that the second polypeptide comprises only one ectodomain of said TNF ligand family member or a fragment thereof. The invention further relates to methods of producing these molecules and to methods of using the same.