Targeted Modified TNF-Superfamily Cytokines for Lower Systemic Toxicity
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Solution Overview
Problem
Systemic administration of TNF superfamily cytokines like TNF and CD95L is hampered by severe toxicity issues, such as shock-inducing properties and lethal hepatotoxicity, limiting their clinical use in cancer treatment, while TRAIL requires combined treatments to achieve therapeutic activity, leading to potential side effects.
Innovation Solution
A construct is developed comprising modified cytokines of the TNF superfamily with reduced affinity to their receptors, linked to a targeting moiety, such as a nanobody, to specifically deliver the cytokine to target cells, reducing systemic toxicity and enhancing therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic administration of TNF superfamily cytokines (TNF, CD95L) is performed, then antitumor activity is achieved, but severe toxicity occurs (shock-inducing properties, lethal hepatotoxicity)
Solution Approach 1:
The cytokine is divided into a single-chain format with separate functional domains: a targeting moiety (nanobody) that directs the cytokine to tumor cells and a cytokine chain with reduced affinity mutations that minimize off-target effects. This segmentation allows the cytokine to be active only at the tumor site while reducing systemic toxicity.
Solution Approach 2:
A nanobody targeting moiety serves as an intermediary between the cytokine and tumor cells. This intermediary directs the cytokine specifically to tumor cells expressing the target antigen, preventing random distribution throughout the body and thereby reducing non-specific toxicity while maintaining antitumor activity.
2Reliability
If TRAIL is administered systemically, then therapeutic activity is achieved, but combined treatments are required leading to potential side effects
Solution Approach 1:
The single-chain cytokine construct combines multiple functions in one molecule: targeting capability through the nanobody domain and cytokine activity through the modified cytokine chain. This multi-functionality eliminates the need for separate combination treatments, as the construct itself provides both targeting and therapeutic effects.
Solution Approach 2:
The patent merges the targeting function and cytokine activity into a single fusion construct. The nanobody targeting moiety is fused to the modified cytokine chain, creating one unified therapeutic agent that performs both functions simultaneously, thereby simplifying the treatment regimen compared to separate combination therapies.
3Object-affected harmful factors
If modified cytokine with reduced affinity is used, then systemic toxicity is reduced, but biological activity may be diminished
Solution Approach 1:
The cytokine construct exhibits different binding characteristics at different locations: at the tumor site, the nanobody targeting moiety concentrates the cytokine where it can bind to death receptors, while at non-target tissues, the reduced affinity mutations prevent binding. This local quality differentiation ensures high activity at the target site while minimizing off-target effects.
Solution Approach 2:
The affinity parameter of the cytokine is deliberately changed through mutations (e.g., Y87Q, I97S, Y115A) to reduce binding strength to TNF receptors. This parameter change decreases systemic toxicity while the nanobody targeting mechanism compensates by ensuring sufficient local concentration at tumor sites to maintain biological activity.
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 modified cytokine construct achieves significant biological activity only on targeted cells, minimizing systemic toxicity and improving therapeutic index, making it suitable for treating various cancers, including solid tumors and hematological cancers, with reduced side effects.
Implementation Method 1
modified cytokine is specifically delivered to target cells... one or more of the chains carry one or more mutations, resulting in a low affinity to the receptor
Implementation Method 2
The targeting is realized by fusion of the modified cytokine of the TNF superfamily to a targeting moiety, preferably an antibody or antibody-like molecule
Data Source
AI summary
The present invention relates to a modified cytokine of the TNF superfamily, with reduced activity to its receptor, wherein said modified cytokine is specifically delivered to target cells. Preferably, said modified cytokine is a single chain variant of the TNF superfamily, even more preferably, one or more of the chains carry one or more mutations, resulting in a low affinity to the receptor, wherein said mutant cytokine is specifically delivered to target cells. The targeting is realized by fusion of the modified cytokine of the TNF superfamily to a targeting moiety, preferably an antibody or antibody-like molecule. The invention relates further to the use of such targeted modified cytokine of the TNF superfamily to treat diseases.