Mutant IL-7 PD-1 Bispecific Immunoconjugate Targeting
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Solution Overview
Problem
Current cytokine immunotherapies face challenges such as toxicity, tumor tolerance, and immunosuppression due to the induction of VLS, AICD, and activation of Treg cells, as well as tumor escape from targeting, which limits their effectiveness in cancer treatment.
Innovation Solution
A mutant form of IL-7 polypeptide is conjugated to an antibody that binds to PD-1, allowing targeted delivery to immune effector cells like cytotoxic T lymphocytes, thereby enhancing the activation of tumor-specific CTLs over immunosuppressive Treg cells and reversing PD-1-induced immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cytokine immunotherapy is used to activate immune cells, then immune response is enhanced, but toxicity and immunosuppression occur due to activation of Treg cells and AICD
Solution Approach 1:
The patent uses a bispecific antibody as an intermediary molecule that simultaneously binds to IL-7 and PD-1. This mediator selectively delivers IL-7 to PD-1+ immune effector cells while blocking PD-1's immunosuppressive function, thereby enhancing cytotoxic T cell activation without inducing Treg cell activation or AICD that occur with conventional cytokine therapy
Solution Approach 2:
The invention applies local quality by directing IL-7 activity specifically to PD-1+ cytotoxic T lymphocytes and memory T cells through the bispecific antibody's targeted binding. This localized delivery ensures IL-7 effects are confined to the desired effector cells rather than acting systemically on all T cell populations, preventing off-target immunosuppression
2Reliability
If IL-7 is delivered systemically to activate tumor-specific T cells, then tumor response increases, but tumor escape from targeting occurs and immunosuppression is induced
Solution Approach 1:
The bispecific antibody serves as a targeted intermediary that bridges IL-7 and PD-1, enabling selective delivery of IL-7 to PD-1+ tumor-infiltrating lymphocytes. This targeted approach prevents tumor escape by ensuring IL-7 reaches the specific effector cells within the tumor microenvironment while blocking PD-1-mediated immunosuppression simultaneously
Solution Approach 2:
The invention applies preliminary action by blocking PD-1's immunosuppressive function before administering IL-7 through the bispecific antibody. This pre-blockade prevents PD-1 from mediating T cell exhaustion and immunosuppression, priming the immune system to respond more effectively to IL-7 stimulation without subsequent suppression
3Quantity of substance
If conventional cytokine therapy is used to expand T cell populations, then immune cell numbers increase, but AICD and Treg cell activation cause immunosuppression
Solution Approach 1:
The bispecific antibody acts as a selective intermediary that delivers IL-7 specifically to PD-1+ effector T cells while excluding Treg cells. This selective mediation expands cytotoxic T cell populations through IL-7-driven proliferation while simultaneously blocking PD-1 to prevent AICD and maintain the functional reliability of the expanded cells
Solution Approach 2:
The invention applies local quality by restricting IL-7's proliferative effects to PD-1+ cytotoxic T lymphocytes and memory T cells through targeted binding. This localized action expands the desired effector population while preventing Treg cell activation and AICD, maintaining immune function reliability during population expansion
Data Source
AI summary
The present invention generally relates to mutant interleukin-7 polypeptides, immunoconjugates, particularly immunoconjugates comprising a mutant interleukin-7 polypeptide and an antibody that binds to PD-1. In addition, the invention relates to polynucleotide molecules encoding the mutant interleukin-7 polypeptides or the immunoconjugates, and vectors and host cells comprising such polynucleotide molecules. The invention further relates to methods for producing the mutant interleukin-7 polypeptides, immunoconjugates, pharmaceutical compositions comprising the same, and uses thereof.