Targeted Chimeric Interferon With Reduced IFNAR Affinity
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Solution Overview
Problem
Existing consensus interferon therapeutics suffer from severe side effects and low patient compliance due to their pharmacokinetic properties, leading to inadequate viral suppression and high dropout rates.
Innovation Solution
Development of chimeric proteins comprising a consensus interferon with reduced affinity for the interferon-α/β receptor (IFNAR) and attached targeting moieties that specifically bind to antigens or receptors of interest, allowing for localized and controlled therapeutic action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If consensus interferon is administered at high concentrations to achieve adequate viral suppression, then therapeutic activity is improved, but side effects increase severely
Solution Approach 1:
The patent applies local quality by creating interferon variants with modified binding properties that selectively target viral-infected cells while sparing healthy cells. The M149A and R150A mutations confer reduced affinity for IFNAR, creating a localized therapeutic effect that improves safety while maintaining antiviral activity against suppressed viruses.
Solution Approach 2:
The patent implements parameter changes by modifying the interferon molecule's binding affinity parameters through specific amino acid substitutions. The M149A and R150A mutations alter the interferon-IFNAR interaction parameters, reducing off-target effects and improving the therapeutic index while maintaining efficacy against suppressed viruses.
2Reliability
If consensus interferon is administered frequently to maintain serum concentration, then therapeutic activity is improved, but patient compliance decreases
Solution Approach 1:
The targeting moiety confers local quality to the interferon variant, enabling it to accumulate preferentially at sites of viral infection. This localized concentration effect allows for less frequent dosing while maintaining therapeutic efficacy, thereby improving patient compliance.
Solution Approach 2:
The targeting moiety acts as an intermediary that mediates the delivery of the interferon variant to viral-infected cells. This intermediary function enhances the pharmacokinetic profile by prolonging serum half-life and improving tissue penetration, reducing the need for frequent administration.
3Duration of action of stationary object
If consensus interferon is administered to achieve sustained serum concentration, then duration of action is improved, but side effects increase
Solution Approach 1:
The patent applies parameter changes by modifying the interferon molecule through M149A and R150A mutations, which alter its binding kinetics to IFNAR. These parameter changes extend serum half-life by reducing off-target binding while maintaining on-target efficacy, thereby prolonging duration of action without proportionally increasing side effects.
Solution Approach 2:
The interferon variant functions as a modified, short-acting therapeutic that is rapidly cleared from circulation after exerting its effect on suppressed viruses. This disposable-like behavior allows for sustained serum concentration through optimized dosing intervals without the cumulative toxicity associated with longer-acting interferons.
4Reliability
If consensus interferon is used with high dosing frequency, then therapeutic activity is improved, but toxicity increases
Solution Approach 1:
The interferon variant with M149A and R150A mutations exhibits local quality by selectively binding to IFNAR on viral-infected cells while having reduced affinity for other cell types. This selective binding pattern maintains high dosing frequency efficacy while reducing systemic toxicity and off-target effects.
Solution Approach 2:
The patent implements parameter changes through amino acid substitutions that modify the interferon's binding affinity parameters. The M149A and R150A mutations create a favorable therapeutic index by reducing non-specific binding parameters while maintaining specific antiviral activity, thereby reducing toxicity even at high dosing frequencies.
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 chimeric proteins exhibit improved safety and therapeutic activity with reduced side effects, increased serum half-life, and targeted delivery to specific cells or tissues, enhancing treatment efficacy for diseases such as cancer and infections.
Implementation Method 1
a variant consensus interferon comprising one or more mutations relative to the amino acid sequence of SEQ ID NO: 2 that confer reduced affinity for interferon-α/β receptor (IFNAR) relative to the unmutated consensus interferon of SEQ ID NO: 2
Implementation Method 2
one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest
Data Source
Figure 1A~1B
Figure 1C~1D
Figure 1E
AI summary
The present invention relates to chimeric proteins comprising a consensus interferon as a signaling agent. In some embodiments, the consensus interferon is modified and comprises one or more mutations. In an embodiment, the modified consensus interferon comprise one or more mutations that reduce its affinity for IFNAR1 and comprises one or more mutations that reduce its affinity for IFNAR2. The present invention provides pharmaceutical compositions comprising the chimeric proteins and their use in the treatment of various diseases. The present invention relates to a method for treating cancer, comprising administering an effective amount of the chimeric protein.