Fc-Free 4-1BB Agonistic Antibodies with PD1 Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current 4-1BB agonistic antibodies for cancer treatment face challenges with systemic administration causing liver toxicity and uncontrollable side effects due to Fc-receptor binding, necessitating new molecules that effectively engage 4-1BB without relying solely on Fc-receptor interactions.
Innovation Solution
Development of 4-1BBL trimer-containing antigen binding molecules combining a PD1-binding moiety with a costimulatory TNF ligand trimer, where one TNF ligand ectodomain is located on a separate polypeptide, forming a stable trimer capable of specific binding to PD1, reducing safety issues compared to conventional 4-1BB agonistic antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional 4-1BB agonistic antibodies are administered systemically, then 4-1BB engagement is achieved, but liver toxicity and uncontrollable side effects occur due to Fc-receptor binding
Solution Approach 1:
The invention extracts the Fc portion from the antibody structure, creating Fc-free 4-1BB agonistic antibody fragments (such as Fab' or (Fab')2). This removes the Fc-receptor binding capability that causes liver toxicity while preserving the antigen-binding and 4-1BB engagement functions through the retained variable regions and hinge domains.
Solution Approach 2:
The invention introduces heterodimerizing domains (such as knob-into-hole mutations or engineered disulfide bonds) as intermediaries to mediate stable dimerization of the Fc-free antibody fragments. This enables controlled oligomerization for enhanced 4-1BB engagement without requiring Fc-receptor interactions, thereby avoiding the harmful effects while maintaining therapeutic efficacy.
2Reliability
If Fc-receptor binding is utilized for 4-1BB agonistic activity, then immune cell activation is enhanced, but safety issues and uncontrollable side effects increase
Solution Approach 1:
The invention removes the Fc portion that mediates Fc-receptor binding, creating Fc-free antibody fragments that can still engage 4-1BB on immune cells through their variable regions. This eliminates the uncontrolled Fc-receptor mediated activation pathways that lead to side effects while preserving the desired 4-1BB dependent immune cell activation.
Solution Approach 2:
The invention modifies the molecular structure by changing the oligomerization state and valency of the 4-1BB binding fragments (e.g., creating monomeric, dimeric, or multimeric forms through controlled heterodimerization). This allows tuning of the activation parameters to achieve effective immune cell activation through 4-1BB while avoiding overactivation and associated side effects.
3Reliability
If bivalent or multivalent 4-1BB engagement is achieved, then antitumor efficacy is improved, but molecular complexity increases
Solution Approach 1:
The invention segments the antibody structure into separate functional modules: variable regions for 4-1BB binding, hinge regions for flexibility, and engineered heterodimerization domains for controlled oligomerization. This modular segmentation allows the molecule to achieve bivalent or multivalent engagement (improving efficacy) while maintaining manageable structural complexity through standardized domain architectures.
Solution Approach 2:
The invention creates composite molecular structures by combining antibody-derived segments (variable regions, hinges) with engineered heterodimerization domains (such as knob-into-hole mutations or disulfide bond systems). This composite approach enables controlled multivalency for enhanced antitumor efficacy while using well-characterized structural elements that simplify production and characterization compared to fully de novo multivalent designs.
Data Source
Figure 1
Figure 2
Figure 3
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 PD1 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.