Bifunctional IL-7 PD-1 Molecule Half-Life Extension
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Recombinant IL-7 cytokine has a poor pharmacokinetic profile due to rapid distribution and elimination, limiting its clinical use, and bifunctional molecules with IL-7 variants face challenges in improving distribution and reducing elimination while maintaining biological efficacy.
Innovation Solution
A bifunctional molecule with an IL-7 variant (IL-7m) conjugated to a PD-1 binding moiety, utilizing a dimeric Fc domain scaffold with a monovalent antigen binding domain, improves pharmacokinetics and targeting efficacy by reducing IL-7 receptor affinity and enhancing half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If recombinant IL-7 is administered, then immune response is enhanced, but half-life is short due to rapid distribution and elimination
Solution Approach 1:
The patent combines IL-7 with an Fc domain to create a fusion protein. The Fc domain enables binding to the neonatal Fc receptor (FcRn), which mediates transcytosis and endosomal recycling, thereby protecting the IL-7 from degradation and extending its circulating half-life from approximately 7 hours to approximately 13 hours.
Solution Approach 2:
The neonatal Fc receptor (FcRn) acts as an intermediary that rescues the IL-7-Fc fusion protein from degradation. Through FcRn-mediated transcytosis and endosomal recycling, the fusion protein is protected from lysosomal degradation and returned to circulation, effectively reducing elimination.
2Duration of action of moving object
If IL-7 is fused to Fc domain to extend half-life, then circulating half-life is prolonged, but frequent injections are still required for biological effect
Solution Approach 1:
The patent merges IL-7 with an Fc domain and further combines it with a PD-1 binding moiety to create a bifunctional molecule. This combination not only extends half-life through FcRn binding but also concentrates the IL-7 at the tumor site via PD-1 targeting, achieving sustained biological effect with reduced injection frequency.
Solution Approach 2:
The patent segments the therapeutic function into two distinct modules: the Fc domain for pharmacokinetic optimization (half-life extension) and the PD-1 binding moiety for targeted delivery. This segmentation allows each module to independently contribute to the overall therapeutic effect, enabling less frequent dosing.
3Quantity of substance
If cytokine is fused to antibody to concentrate at target, then targeting efficacy is improved, but rapid elimination occurs due to target-mediated drug disposition
Solution Approach 1:
The patent modifies the affinity parameters of the IL-7 component through the Fc domain fusion, which changes the pharmacokinetic profile. The Fc domain reduces the overall affinity for the IL-7 receptor compared to native IL-7, thereby reducing target-mediated drug disposition and rapid depletion, while still maintaining sufficient targeting capability.
4Reliability
If bifunctional molecule with IL-7 variant is designed, then pharmacokinetics are improved, but manufacturing complexity increases
Solution Approach 1:
The patent uses the Fc domain, which is a universal and well-characterized component from antibody technology, to provide multiple functions: extending half-life through FcRn binding, enabling dimerization, and facilitating purification. This multi-functionality reduces the need for separate optimization of each function, thereby managing complexity.
Solution Approach 2:
The patent employs a dimeric Fc domain scaffold that promotes homogeneous assembly of the bifunctional molecule. The symmetric structure of the Fc domain facilitates proper pairing and reduces the formation of heterogeneous aggregates, simplifying manufacturing and purification processes.
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 bifunctional molecule achieves improved pharmacokinetics and in vivo anti-tumor efficacy with enhanced targeting of tumor-specific T cells, blocking suppressive Treg activity, and restoring exhausted T cell function, leading to increased survival and reduced tumor growth.
Implementation Method 1
the IgG can bind neonatal Fc receptor (FcRn) and engage transcytosis and endosomal recycling of the molecule
Implementation Method 2
the affinity of IL-7 cytokine for its CD127/CD132 receptor (nanomolar to picomolar range) may be higher than the affinity of the antibody for its target. Hence, the cytokine will drive the pharmacokinetics of the product leading to a fast depletion of the available drug in vivo due to the target-mediated drug disposition (TMDD) mechanism
Data Source
AI summary
The present invention relates to bifunctional molecules comprising an IL-7 variant and having a particular scaffold and their uses.