Chimeric Cytokine-Binding Polypeptides for CRS Mitigation in Immunotherapy
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Solution Overview
Problem
Existing immunotherapies, such as cancer immunotherapy, often cause cytokine release syndrome (CRS) with side effects like hypotension and fever, necessitating treatments to prevent or alleviate these toxicities.
Innovation Solution
Development of chimeric tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) binding polypeptides, along with IL-1 receptor binding polypeptides and chimeric antigen receptors (CARs), administered to patients to reduce CRS risk and toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunotherapy is administered to treat cancer, then therapeutic efficacy is improved, but cytokine release syndrome (CRS) and toxicity occur
Solution Approach 1:
The patent introduces chimeric binding polypeptides as intermediary molecules that specifically bind to and neutralize cytokines (TNF-α, IFN-γ, IL-1) responsible for CRS. These polypeptides act as mediators between the immunotherapy and the patient's immune system, blocking harmful cytokine signaling while allowing therapeutic effects to proceed. The binding polypeptides include variable regions from antibodies that specifically recognize and bind to these cytokines, preventing them from interacting with their receptors and causing CRS.
2Productivity
If T-cell engaging therapies are used, then cancer treatment effectiveness is improved, but side effects such as hypotension and fever occur
Solution Approach 1:
The patent converts the harmful cytokine storm into a beneficial effect by using the same cytokine-binding mechanisms that cause CRS to instead protect patients. The chimeric binding polypeptides are designed to specifically capture and neutralize the excessive cytokines produced during T-cell activation, transforming the harmful inflammatory response into a controlled therapeutic effect. This allows the immunotherapy to proceed at full effectiveness while the binding polypeptides mop up the harmful cytokines.
3Object-affected harmful factors
If cytokine binding polypeptides are administered to prevent CRS, then toxicity is reduced, but therapeutic efficacy may be compromised
Solution Approach 1:
The patent applies local quality by designing binding polypeptides with specific affinities for different cytokines (TNF-α, IFN-γ, IL-1) that are locally overexpressed during CRS. Rather than broadly suppressing all immune activity, the polypeptides selectively bind to and neutralize only the specific cytokines responsible for harmful effects at specific locations and times. This localized, selective approach preserves overall therapeutic efficacy while preventing CRS.
Solution Approach 2:
The patent incorporates dynamic regulation by designing the chimeric binding polypeptides to be inducible or conditionally expressed. The polypeptides can be activated or upregulated in response to cytokine presence, allowing them to dynamically respond to the immune response intensity. This ensures that therapeutic efficacy is maintained during normal immune function while CRS prevention occurs when cytokine levels become excessive.
Data Source
AI summary
The current disclosure provides polypeptide, nucleic acid, compositions, and methods for treating or preventing CRS in patients in need thereof, particularly for those receiving an immunotherapy, such as a cancer immunotherapy, that may provoke a CRS response. Accordingly, aspects of the disclosure relate to a chimeric binding polypeptides comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 attached by a heterologous linker to a light chain variable region comprising CDR4, CDR5, and CDR6.