Fc Backbone Fusion Protein Dimer for Targeted Cytokine Delivery
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Solution Overview
Problem
Cytokine-based immunotherapy is hindered by severe side effects and poor pharmacokinetic properties, and existing antibody fusion methods often reduce the activity of antibodies, limiting their therapeutic effectiveness, especially when used in combination for optimal effects.
Innovation Solution
A fusion protein dimer is developed using an antibody Fc region as a backbone, incorporating single-domain antibodies and cytokines like IL-2 and IL-12, linked through linker sequences, to enhance targeting specificity and reduce cytotoxicity, forming either homodimers or heterodimers with asymmetric complementary structures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If cytokines are fused to antibody through conventional methods, then targeted delivery is improved, but the activity of the antibody is reduced
Solution Approach 1:
The invention divides the antibody structure into separate domains, fusing cytokines to the Fc region while keeping the antigen-binding variable regions intact and independent. This segmentation allows the antibody to maintain its binding activity while the Fc region delivers the cytokine function, resolving the contradiction between targeted delivery and antibody activity preservation.
Solution Approach 2:
The Fc region serves as an intermediary element that connects the antibody's targeting function with the cytokine's therapeutic function. By positioning the cytokine fusion at the Fc region rather than interfering with the variable regions, the intermediary Fc domain enables both targeted delivery and preservation of antibody activity.
2Reliability
If cytokine-based immunotherapy is used, then immune regulation function is enhanced, but severe side effects occur
Solution Approach 1:
The antibody component performs preliminary targeting action by specifically binding to antigens on tumor cells or immune cells, ensuring that the cytokine is delivered precisely to the intended site. This preliminary targeting prevents systemic distribution of the cytokine, thereby enhancing immune regulation at the target site while minimizing side effects in healthy tissues.
Solution Approach 2:
The fusion protein structure acts as an intermediary delivery system, carrying the cytokine to specific targets through the antibody's specificity. This mediated delivery ensures that the cytokine's immune regulation function is activated primarily at the target site, reducing harmful side effects while maintaining therapeutic efficacy.
3Duration of action of stationary object
If cytokines are fused to antibody, then pharmacokinetic properties are improved, but cytotoxicity increases
Solution Approach 1:
By segmenting the fusion construct to place the cytokine at the Fc region rather than integrating it into the antigen-binding domain, the invention allows the antibody to maintain its pharmacokinetic advantages (long circulation half-life, efficient tissue penetration) while directing cytokine activity specifically to target cells through antigen binding, thereby reducing off-target cytotoxicity.
Solution Approach 2:
The antibody portion performs preliminary site-specific binding before cytokine release or activation, ensuring that the pharmacokinetic benefits of the antibody (extended circulation, targeted accumulation) are utilized while the cytokine's cytotoxic effect is confined to the target site, minimizing harmful effects on non-target cells.
Data Source
AI summary
Provided is a fusion protein dimer using an antibody Fc region as the backbone, comprising a first and a second polypeptide chain. The first polypeptide chain comprises a first antibody Fc region and one or more single-domain antibodies fused to the first antibody Fc region. The second polypeptide chain comprises a second antibody Fc region and one or more single domain antibodies fused to the second antibody Fc region. The first polypeptide chain and/or the second polypeptide chain further comprise a cytokine fused to the Fc region of the respective antibody. Further provided is use of the fusion protein dimer in preparing an immunotherapeutic drug for treating tumors. The Fc fusion protein heterodimer not only increases the activity of a single domain antibody, but also significantly improves the biological activity of a cytokine. Further, by means of the targeting specificity of the antibody, the targeted transport of the cytokine is effectively enhanced, and cytotoxicity is attenuated, thereby obtaining better anti-tumor potential.