Bifunctional Molecule Blocking TGFβ and PD-L1
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Solution Overview
Problem
Current cancer treatments using PD-1/PD-L1 monoclonal antibodies have limited response rates and often require combination with chemotherapy or radiotherapy, increasing toxicity and reducing patient compliance, with some patients not responding to treatment due to immune evasion mechanisms involving TGFβ and PD-L1 pathways.
Innovation Solution
Development of a bifunctional molecule comprising human TGFβRII or its functional fragment and an antibody or antigen-binding fragment targeting PD-L1, with specific amino acid sequences for CDRs and framework regions, to simultaneously bind to TGFβ and PD-L1, potentially enhancing anti-tumor activity by blocking TGFβ and promoting immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If PD-1/PD-L1 monoclonal antibody is used alone, then the treatment is simple, but the objective response rate is not high
Solution Approach 1:
The patent merges PD-L1 blocking function with TGFβ inhibition function into a single bifunctional molecule. The molecule contains both an anti-PD-L1 antibody component and a TGFβ binding component (such as soluble TGFβ receptor), enabling simultaneous blockade of both immune checkpoint and TGFβ signaling pathways in one therapeutic agent, thereby improving response rate while maintaining treatment simplicity
Solution Approach 2:
The bifunctional molecule performs multiple therapeutic functions simultaneously: it blocks PD-L1 to enhance T cell activation, inhibits TGFβ to reverse immunosuppression, and can recruit immune cells to the tumor microenvironment. This multi-functionality addresses the limitation of single-function antibodies by providing comprehensive immunotherapy in one molecule
2Reliability
If PD-1/PD-L1 monoclonal antibody is combined with chemotherapy or radiotherapy, then the response rate may improve, but toxicity increases and patient compliance reduces
Solution Approach 1:
Instead of combining separate PD-1/PD-L1 antibody with chemotherapy or radiotherapy (which increases toxicity), the patent combines PD-L1 blocking and TGFβ inhibition functions into one bifunctional molecule. This integrated approach achieves synergistic anti-tumor effects through dual pathway blockade without the additional toxicities associated with chemotherapy or radiotherapy
Solution Approach 2:
The patent converts the harmful immunosuppressive effect of TGFβ (which limits PD-1/PD-L1 antibody efficacy) into a beneficial target. By specifically inhibiting TGFβ signaling within the bifunctional molecule, the therapy transforms the tumor microenvironment's immunosuppressive advantage into an opportunity for enhanced T cell activation and tumor regression
3Reliability
If PD-1/PD-L1 monoclonal antibody is used, then some patients respond to treatment, but some patients have no response due to immune evasion mechanisms
Solution Approach 1:
The bifunctional molecule is designed to address multiple immune evasion mechanisms simultaneously through its dual functionality: PD-L1 blocking overcomes checkpoint-mediated suppression, while TGFβ inhibition reverses T cell exhaustion and fibrosis in the tumor microenvironment. This broad mechanism of action increases applicability across diverse patient populations with different immune evasion strategies
Solution Approach 2:
The patent changes the therapeutic parameter from single-target blockade to dual-pathway inhibition. By simultaneously targeting PD-L1 and TGFβ signaling pathways, the bifunctional molecule creates a more robust immunotherapeutic effect that can overcome heterogeneous immune evasion mechanisms employed by different tumor types and patient populations
Data Source
AI summary
Provided are a bifunctional molecule capable of binding to human transforming growth factor β (TGFβ) and human programmed death-ligand 1 (PD-L1), a pharmaceutical composition comprising the same, and use thereof treating cancer. The bifunctional molecule has high affinity for PD-L1, can significantly promote the secretion of IL-2 and IFN-γ, enhances T cell immune responses, and can block TGFβ with high specificity, and thus can be used for treating cancer. Also provided is a monoclonal antibody or an antigen-binding fragment thereof binding to human PD-L1.