PD-L1 Chimeric Antigen Multimers for Cancer Immunotherapy
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Solution Overview
Problem
Current PD-L1-based immunotherapies for cancer treatment face challenges such as high costs, adverse effects, and limited immunogenicity, requiring frequent administration of high doses of monoclonal antibodies and inducing only moderate immune responses, which can lead to immune tolerance and reduced efficacy.
Innovation Solution
A chimeric antigen comprising the extracellular domain of PD-L1, engineered to form multimeric aggregates with reduced binding capacity to PD-1 and CD80 receptors, enhancing immunogenicity and safety by promoting a vigorous humoral and cellular immune response without the need for increased antigen doses, achieved through structural aggregation and combination with adjuvants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-PD-L1 monoclonal antibodies are used for cancer treatment, then the immune response is blocked and tumor growth is inhibited, but frequent administration and high doses are required leading to high costs and adverse effects
Solution Approach 1:
The patent changes the molecular parameters of the PD-L1 antigen by creating fusion proteins with altered structural properties. The fusion constructs (e.g., PD-L1-Fc, PD-L1-mIgG2a) modify the pharmacokinetic and immunogenic parameters of PD-L1, enabling sustained immune response with reduced dosing frequency and lower doses compared to monoclonal antibodies.
Solution Approach 2:
The patent employs composite antigen structures by fusing PD-L1 extracellular domain with other protein domains (such as Fc region of IgG). This composite approach creates multimeric structures that enhance immunogenicity and prolong half-life, reducing the need for frequent high-dose administrations and associated adverse effects.
2Reliability
If polypeptides covering most of the PD-L1 protein or their peptides are used as active immunotherapy, then the immune response is stimulated, but the immunogenicity is limited and immune tolerance develops
Solution Approach 1:
The patent merges the PD-L1 extracellular domain with additional protein structures (such as Fc regions) to create fusion proteins. This combining approach generates novel antigenic determinants that maintain PD-L1-specific immunogenicity while avoiding immune tolerance, as the composite structure presents multiple epitopes that sustain adaptive immune responses.
3Reliability
If high doses of antigen are administered to overcome immune tolerance, then the immune response is enhanced, but the cost and potential adverse effects increase
Solution Approach 1:
The patent alters the structural parameters of the PD-L1 antigen through fusion protein construction, which changes its immunogenic properties. These parameter changes enable the antigen to elicit stronger immune responses at lower doses, reducing the quantity of substance required while maintaining or enhancing therapeutic efficacy.
Data Source
AI summary
Chimeric antigen comprising multimeric aggregates of the extracellular domain of the programmed death ligand 1 (PD-L1) with a reduced binding capacity to the PD-1 and CD80 receptors as compared to the native PD-L1 molecule. The invention further discloses pharmaceutical compositions including said chimeric antigen and at least a pharmaceutically acceptable vaccine adjuvant. The chimeric antigen is used for the manufacturing of a drug to treat cancer or its metastases. The invention also discloses a method of treating cancer or its metastases in a subject in need thereof, characterized by the administration of a therapeutically effective amount of the pharmaceutical composition comprising the chimeric antigen described herein.