LIGHT Mutein Receptor Selectivity for Lower-Toxicity Immunotherapy
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Solution Overview
Problem
Existing cancer immunotherapy strategies using LIGHT protein as a therapeutic agent face challenges in selectively interacting with its receptors, leading to potential toxicity due to non-specific binding to decoy receptor 3 (DcR3).
Innovation Solution
Development of LIGHT muteins with specific amino acid mutations that enhance binding to lymphotoxin beta receptor (LTβR) and herpes virus entry mediator (HVEM) while reducing affinity for DcR3, thereby optimizing therapeutic efficacy and minimizing toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If LIGHT protein is used as a therapeutic agent for cancer immunotherapy, then therapeutic efficacy is improved through interaction with receptors LTβR and HVEM, but toxicity increases due to non-specific binding to decoy receptor DcR3
Solution Approach 1:
The patent applies local quality by introducing specific amino acid mutations at particular positions (e.g., L158Q, L158P, L158M, S160G, S160N, S160T, S160A, T161G, T161P, T161S, T161N) within the LIGHT protein sequence to selectively modify its binding properties. These localized changes enhance affinity for LTβR and HVEM while reducing binding to DcR3, thereby improving therapeutic efficacy without proportionally increasing toxicity.
Solution Approach 2:
The patent employs parameter changes by systematically varying the amino acid sequence parameters of LIGHT through multiple mutation combinations. By changing specific residues at defined positions, the patent optimizes the binding parameters (affinity and specificity) of LIGHT for its intended receptors while minimizing off-target binding to DcR3, thus resolving the contradiction between efficacy and toxicity.
2Adaptability or versatility
If LIGHT protein binds to multiple receptors including DcR3, then broader biological activity is achieved, but selectivity is reduced leading to increased side effects
Solution Approach 1:
The patent applies local quality by introducing specific amino acid mutations at particular positions (e.g., L158Q, L158P, L158M, S160G, S160N, S160T, S160A, T161G, T161P, T161S, T161N) within the LIGHT protein sequence to selectively modify its binding properties. These localized changes enhance affinity for LTβR and HVEM while reducing binding to DcR3, thereby improving therapeutic efficacy without proportionally increasing toxicity.
Solution Approach 2:
The patent employs parameter changes by systematically varying the amino acid sequence parameters of LIGHT through multiple mutation combinations. By changing specific residues at defined positions, the patent optimizes the binding parameters (affinity and specificity) of LIGHT for its intended receptors while minimizing off-target binding to DcR3, thus resolving the contradiction between efficacy and toxicity.
Data Source
AI summary
The present disclosure provides a LIGHT mutein and a LTβR binding LIGHT mutein, and it also provides a related polynucleotide, an isolated vector, a host cell, and a pharmaceutical composition. Further, the present disclosure provides the use of the LIGHT mutein or the isolated polynucleotide, the isolated vector, the host cell, or the pharmaceutical composition in the manufacture of a drug for preventing or treating a disease, and a method of preventing or treating a disease in a subject in need thereof.