Fusion Polypeptide with Fc and Costimulatory Domains for PD-1 Blockade
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Solution Overview
Problem
Current PD-1/PD-L1 pathway blockade therapies for tumors have limited effectiveness, with an average treatment response rate of about 20%, and many tumor patients do not respond to anti-PD-L1 or anti-PD-1 antibodies, necessitating the development of agents that can synergize with PD-1/PD-L1 blockade to enhance T cell activation and improve treatment efficacy.
Innovation Solution
Development of a fusion polypeptide comprising antibody-associated antigen binding fragments, immunoglobulin Fc domains, and CD80 or LAG3 extracellular domains to block PD-1/PD-L1 signaling, stimulate antigen-presenting cells, and activate T cells, thereby enhancing immune response and tumor-killing effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-PD-L1 or anti-PD-1 antibodies are used for tumor treatment, then immune response regulation is achieved, but treatment effectiveness is limited with only about 20% response rate
Solution Approach 1:
The patent combines multiple functional domains into a single fusion polypeptide: an antigen-binding fragment (anti-PD-L1 or anti-PD-1), an Fc domain for immune modulation, and a costimulatory domain (CD80 or LAG3). This merging of functions allows the single molecule to simultaneously block PD-1/PD-L1 interactions, engage Fc receptors for enhanced immune activation, and provide costimulatory signals, thereby overcoming the limited effectiveness of monotherapy antibodies.
Solution Approach 2:
The fusion polypeptide is designed with multi-functionality to address different aspects of immune suppression: the antigen-binding fragment blocks PD-1/PD-L1 signaling, the Fc domain enables binding to Fc receptors on immune cells for enhanced activation and antibody-dependent cellular cytotoxicity, and the costimulatory domain (CD80 binding to CD28 or LAG3 binding to MHC II) provides additional activation signals. This multi-functional design aims to increase the proportion of patients who respond to treatment.
2Reliability
If existing anti-PD-L1 or anti-PD-1 antibodies are administered, then some tumor treatment effect is achieved, but a considerable number of patients do not respond to treatment
Solution Approach 1:
By merging multiple immune-modulating functions into one fusion polypeptide, the invention creates an agent that can work through multiple pathways simultaneously. This increases the likelihood of achieving therapeutic effect across diverse patient populations with different tumor microenvironments and immune profiles, thereby reducing the non-response rate observed with single-antibody therapies.
Solution Approach 2:
The fusion polypeptide represents a composite molecular structure combining different protein domains with distinct functions. This composite design allows the molecule to engage multiple immune cell types and signaling pathways, providing a more robust and adaptable therapeutic effect across different patient populations and tumor types.
3Reliability
If fusion polypeptide with multiple domains is developed, then T cell activation and immune response are enhanced, but molecular structure complexity increases
Solution Approach 1:
The invention merges multiple functional domains (antigen-binding fragment, Fc domain, costimulatory domain) into a single fusion polypeptide chain. While this increases structural complexity, it consolidates multiple functions into one molecule, potentially simplifying administration and pharmacokinetics compared to using multiple separate antibodies or agents.
Solution Approach 2:
The multi-domain fusion polypeptide achieves multi-functionality within a single molecular entity. The antigen-binding fragment provides target specificity, the Fc domain enables immune cell engagement and modulation, and the costimulatory domain enhances T cell activation. This integrated design aims to enhance immune response while maintaining a manageable structural framework through standardized domain architectures.
Data Source
AI summary
The present application relates to a fusion polypeptide and its use. Specifically, the fusion polypeptide of the present application can block PD-1/PD-L1 signaling and/or can have the function of activating an immune response. The application also provides the use of the polypeptide.