Fc Domain Engineering for Targeted 4-1BB Agonists
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Solution Overview
Problem
Current 4-1BB agonistic antibodies induce liver toxicity and uncontrollable side effects due to systemic Fc-receptor binding, necessitating the development of new drug candidates that effectively engage 4-1BB without relying solely on Fc-receptor interactions.
Innovation Solution
Design and production of 4-1BB ligand trimer-containing antigen binding molecules comprising a Fab domain for specific binding to tumor-specific or tumor-associated targets, combined with a stable Fc domain and peptide-linked 4-1BBL ectodomains, which form a biologically active TNF ligand trimer, reducing Fc-receptor binding and enhancing tumor specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If 4-1BB agonistic antibodies are used to activate 4-1BB, then anti-tumor effects are improved, but liver toxicity and uncontrollable side effects occur due to systemic Fc-receptor binding
Solution Approach 1:
The patent extracts the harmful Fc-receptor binding function from the antibody molecule by using Fc domain variants with reduced or eliminated Fc-receptor binding capability. The Fc domain is retained for structural stability and trimer formation, but its harmful interaction with Fc-receptors is removed through specific amino acid substitutions, thereby eliminating liver toxicity while preserving anti-tumor efficacy through 4-1BB activation.
Solution Approach 2:
The patent applies local quality by modifying specific regions of the Fc domain (through amino acid substitutions) to alter its binding properties. The Fc domain is engineered to have reduced Fc-receptor binding affinity in specific locations while maintaining its ability to support trimer formation and structural integrity, creating a localized functional differentiation that resolves the contradiction between efficacy and toxicity.
2Object-affected harmful factors
If Fc-receptor binding is reduced to minimize toxicity, then harmful factors are decreased, but stability and structural integrity of the molecule may be compromised
Solution Approach 1:
The patent segments the Fc domain into distinct functional regions: one portion (the Fc domain backbone) maintains structural stability and supports trimer formation, while another portion (specific amino acid residues) is modified to reduce Fc-receptor binding. This segmentation allows independent optimization of stability and reduced toxicity without compromising either function.
Solution Approach 2:
The patent changes specific parameters of the Fc domain through amino acid substitutions that selectively reduce Fc-receptor binding affinity while preserving the structural parameters necessary for stability. The molecular weight, charge distribution, and conformational properties are adjusted through targeted substitutions to achieve reduced toxicity without sacrificing structural integrity.
3Reliability
If TNF ligand trimers are formed to enhance 4-1BB activation, then biological activity is improved, but complexity of molecule structure increases
Solution Approach 1:
The patent merges the 4-1BBL ectodomain with the Fc domain to create a fusion protein that self-assembles into trimers. The Fc domain serves dual purposes: providing structural stability and enabling trimer formation through its natural dimerization capability combined with the trimeric 4-1BBL ectodomain. This merging eliminates the need for separate trimerization domains or complex assembly mechanisms, reducing overall molecular complexity while maintaining enhanced 4-1BB activation.
Data Source
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AI summary
The invention relates to novel TNF family ligand trimer-containing antigen binding molecules comprising (a) one Fab domain capable of specific binding to a target cell antigen, (b) a Fc domain composed of a first and a second subunit capable of stable association, and (c) a first polypeptide comprising two ectodomains of a TNF ligand family member or fragments thereof that are connected to each other by a peptide linker and a second polypeptide comprising one ectodomain of said TNF ligand family member or a fragment thereof, wherein the first polypeptide is fused at its N-terminus to the C-terminus of one of the subunits of the Fc domain and wherein the second polypeptide is fused at its N-terminus to the C-terminus of the other subunit of the Fc domain, wherein the TNF family ligand trimer-containing antigen binding molecule is monovalent for the binding to the target cell antigen.