Single Effector Immunoconjugate Reduces Systemic Toxicity
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Solution Overview
Problem
Conventional immunoglobulin-cytokine immunoconjugates have high avidity to cytokine receptors due to multiple cytokine moieties, leading to targeting of immune effector cells rather than the intended antigen, causing systemic toxicity and infusion reactions, and have short half-lives and stability issues.
Innovation Solution
Development of immunoglobulin-like immunoconjugates with a single effector moiety fused to an Fc domain, featuring altered binding to Fc receptors and oligosaccharide structures to enhance specificity and stability, and incorporating modifications such as knob-into-hole heterodimerization and amino acid substitutions to reduce systemic toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple cytokine moieties are coupled to immunoglobulin heavy chains, then the immunoconjugate has high avidity to cytokine receptors, but it targets immune effector cells rather than the intended antigen, causing systemic toxicity
Solution Approach 1:
The invention divides the conventional structure with multiple cytokine moieties into a segmented structure with only one cytokine moiety coupled to the immunoglobulin heavy chain. This segmentation reduces the avidity to cytokine receptors, preventing activation of immune effector cells and the resulting systemic toxicity, while preserving the targeting function through the antigen-specific immunoglobulin portion.
Solution Approach 2:
The invention extracts the excess cytokine moieties from the conventional immunoconjugate structure, retaining only a single cytokine moiety. This extraction eliminates the harmful over-activation of cytokine receptors on immune effector cells, thereby resolving the systemic toxicity issue while maintaining sufficient therapeutic effect through the single retained cytokine moiety.
2Reliability
If high doses of cytokine are administered systemically to achieve sufficient concentration at tumor site, then anti-tumor effect is achieved, but severe toxicity and adverse reactions occur
Solution Approach 1:
The invention uses the immunoglobulin heavy chain as an intermediary carrier to deliver the cytokine moiety specifically to the tumor site. The antigen-specific immunoglobulin portion acts as a mediator that guides the cytokine to the intended target, eliminating the need for high systemic doses and thereby preventing severe toxicity while maintaining anti-tumor efficacy.
Solution Approach 2:
The invention creates local concentration of the cytokine at the tumor site through targeted delivery, rather than distributing it systemically. The single cytokine moiety coupled to the antigen-specific immunoglobulin accumulates locally at the tumor, providing sufficient therapeutic effect without the systemic exposure that causes severe toxicity.
3Reliability
If conventional immunoconjugates are used, then cytokines are delivered to specific sites, but infusion reactions occur due to activation of cytokine receptors on immune effector cells in peripheral blood
Solution Approach 1:
The invention segments the cytokine delivery system to include only one cytokine moiety per immunoglobulin heavy chain, rather than multiple moieties. This segmentation reduces the overall avidity to cytokine receptors on immune effector cells in peripheral blood, preventing their activation and the subsequent infusion reactions, while preserving the tumor targeting capability.
4Reliability
If immunoglobulin-cytokine fusion proteins are used to maximize therapeutic activity, then beneficial effects at tumor site are enhanced, but the structure has disadvantages including high cytokine receptor avidity
Solution Approach 1:
The invention extracts the excessive cytokine moieties from the fusion protein structure, retaining only one cytokine moiety per immunoglobulin heavy chain. This simplification reduces the structural complexity and the harmful high avidity to cytokine receptors, while preserving the essential therapeutic activity through the retained cytokine moiety and the Fc domain-mediated immune effector cell activation.
Data Source
AI summary
The present invention generally relates to antigen-specific immunoconjugates for selectively delivering effector moieties that influence cellular activity. More specifically, the invention provides novel immunoconjugates comprising a first antigen binding moiety, an Fc domain and a single effector moiety. In addition, the present invention relates to polynucleotides encoding such immunoconjugates, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the immunoconjugates of the invention, and to methods of using these immunoconjugates in the treatment of disease.