TNF Ligand Trimer Antigen-Binding Molecules Without Fc-Receptor Binding
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Solution Overview
Problem
Existing 4-1BB agonistic antibodies for cancer treatment induce liver toxicity and other side effects due to systemic administration through Fc-receptor binding, necessitating the development of new antigen binding molecules that can preferentially bind to tumor-specific targets and form a costimulatory TNF ligand trimer without relying on Fc-receptor interaction.
Innovation Solution
A TNF family ligand trimer-containing antigen binding molecule comprising two ectodomains of a TNF ligand family member connected by a peptide linker and one ectodomain linked via a disulfide bond, with an Fc domain for stable association, designed to specifically bind to tumor-associated antigens and form a biologically active trimer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If 4-1BB agonistic antibodies are administered systemically for cancer treatment, then T-cell activation and anti-tumor responses are stimulated, but liver toxicity and other side effects occur due to Fc-receptor binding
Solution Approach 1:
The patent extracts and removes the Fc domain from the antibody structure, retaining only the antigen-binding Fab regions. This eliminates the Fc-receptor interaction that causes liver toxicity while preserving the ability to bind tumor-associated antigens and form trimers that stimulate T-cell activation.
Solution Approach 2:
The invention modifies the local quality of the antibody by creating heterogeneity in the polypeptide chains - some chains contain the full Fc domain while others contain only the Fab region. This local modification allows the molecule to bind antigens and form trimers without engaging Fc-receptors, thereby reducing systemic toxicity.
2Stability of the object's composition
If Fc domain is included in the antibody structure for stable association, then molecular stability is improved, but Fc-receptor binding causes systemic side effects
Solution Approach 1:
The antibody molecule is segmented into distinct polypeptide chains with different functions. Some chains provide structural stability through the Fc domain, while other chains eliminate Fc-receptor binding. This segmentation allows the molecule to achieve stability without the harmful Fc-receptor interactions.
Solution Approach 2:
The patent creates a composite antibody structure combining different polypeptide chain types - full-length chains with Fc domains for stability and truncated chains without Fc domains to avoid Fc-receptor binding. This composite structure achieves both molecular stability and reduced toxicity.
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 molecule effectively stimulates T-cell activation and anti-tumor responses while minimizing side effects by avoiding Fc-receptor binding, enhancing therapeutic efficacy with reduced toxicity.
Implementation Method 1
a first and a second polypeptide that are linked to each other by a disulfide bond
Implementation Method 2
Members of the TNF ligand family exert their biological function as self-assembling, noncovalent trimers
Data Source
AI summary
The invention relates to novel TNF family ligand trimer-containing antigen binding molecules comprising (a) at least one moiety capable of specific binding to a target cell antigen and (b) a first and a second polypeptide that are linked to each other by a disulfide bond, characterized in that the first polypeptide comprises two ectodomains of a TNF ligand family member or 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.