Fusion Protein Targeting PD-L1 and CD47 for Tumor Inhibition
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Solution Overview
Problem
Current therapies for tumors, particularly those targeting PD-1 and CD47, have limited efficacy due to insufficient recognition activity and adverse side effects, necessitating a more effective approach that simultaneously targets PD-L1 and CD47 to inhibit tumor growth.
Innovation Solution
A fusion protein is developed, comprising a first binding domain that specifically binds PD-L1 and a second binding domain that specifically binds CD47, utilizing a mutant of the human SIRPα variant 1 with amino acid substitutions at specific positions, allowing for simultaneous binding and blocking of PD-L1 and CD47 interactions, thereby inhibiting tumor growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-1 or PD-L1 inhibitors are used alone, then immunotherapy effect is achieved, but clinical response rate is low and side effects occur
Solution Approach 1:
The patent combines PD-L1 binding domain and CD47 binding domain into a single fusion protein molecule, enabling simultaneous targeting of both PD-L1 on tumor cells and CD47 on tumor cells. This merging approach enhances antitumor efficacy through dual mechanism while potentially reducing the need for multiple separate therapies that could increase side effects
Solution Approach 2:
The fusion protein is constructed as a composite molecular structure with distinct functional domains: a PD-L1 binding domain (antibody-derived) and a CD47 binding domain (SIRPα-based). This composite design allows the single molecule to exert multiple therapeutic functions - blocking PD-1/PD-L1 interaction and blocking CD47/SIRPα interaction - thereby improving clinical response rate through synergistic effects
2Reliability
If current CD47-targeting antibodies are used, then tumor growth inhibition is achieved, but recognition activity is limited and affinities with CD47 are insufficient
Solution Approach 1:
The patent modifies the SIRPα protein by introducing amino acid substitutions at specific positions (e.g., L106P, Q108R, N101K) to enhance its binding affinity for CD47. These parameter changes in the molecular structure of the CD47-binding domain transform the otherwise low-affinity interaction into a high-affinity binding, thereby improving tumor growth inhibition efficacy
Solution Approach 2:
The fusion protein employs a localized modification strategy where only specific regions of the SIRPα protein (the CD47-binding domain) are mutated to improve CD47 affinity, while the overall structure and PD-L1 binding domain remain intact. This local quality enhancement allows selective optimization of CD47 binding without compromising other functional properties
3Reliability
If current CD47-targeting antibodies are used, then tumor growth inhibition is attempted, but anemia responses or thrombocytopenia side effects occur
Solution Approach 1:
The fusion protein merges PD-L1 targeting and CD47 targeting into one molecule, enabling the therapy to achieve tumor growth inhibition through dual mechanisms. By combining these functions, the patent may achieve effective tumor control at lower doses, potentially reducing off-target effects and hematological toxicities associated with high-dose CD47 inhibitors
Solution Approach 2:
The fusion protein acts as an intermediary that simultaneously blocks two immune checkpoints (PD-1/PD-L1 and CD47/SIRPα) that tumors exploit for evasion. By mediating dual blockade, the therapy achieves more comprehensive immune activation and tumor suppression, potentially allowing for reduced dosing and minimized side effects compared to monotherapies
Data Source
AI summary
Provided are a fusion protein, and an immunoconjugate, a nucleic acid molecule, a carrier, a composition, a cell and a preparation method related thereto, for treating tumors and/or autoimmune diseases.