IL-2 Redirecting Polypeptide Constructs for Targeted Cancer Therapy
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Solution Overview
Problem
Current methods for enhancing anti-tumor immune responses, such as using interleukin 2 (IL-2), often result in toxic side effects and require frequent dosing due to short half-life, limiting their effectiveness and safety.
Innovation Solution
Development of polypeptide constructs comprising a targeting moiety, like PD-1 binding antibodies, fused with a CD25 moiety to redirect IL-2 binding to PD-1 expressing cells, thereby amplifying anti-tumor immune responses without systemic toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic IL-2 administration is used to enhance anti-tumor immune response, then anti-tumor immunity is enhanced, but toxic side effects and generalized immune activation occur
Solution Approach 1:
The patent applies local quality by creating a targeted delivery system where IL-2 is specifically directed to tumor cells through antibody-IL-2 conjugates. The antibody component binds selectively to tumor-associated antigens, ensuring that IL-2 is released and acts locally at the tumor site rather than systemically, thereby enhancing anti-tumor immunity while minimizing toxic side effects
Solution Approach 2:
The patent uses an antibody as an intermediary molecule that bridges the gap between systemic IL-2 administration and localized tumor targeting. The antibody-IL-2 conjugate acts as a mediator that carries IL-2 to the tumor site, where the antibody binds to tumor antigens and releases IL-2 locally, thus achieving targeted immunotherapy without the need for direct systemic IL-2 injection
2Reliability
If IL-2 is administered systemically to achieve therapeutic effect, then anti-tumor immunity is enhanced, but frequent dosing is required due to short half-life
Solution Approach 1:
The patent applies preliminary action by pre-conjugating IL-2 with tumor-targeting antibodies before administration. This pre-prepared conjugate ensures that upon injection, the IL-2 is immediately directed to tumor cells without requiring distribution throughout the body first, thereby reducing the need for frequent dosing while maintaining therapeutic efficacy
Solution Approach 2:
The patent achieves continuity of useful action through the sustained localized release of IL-2 at the tumor site. The antibody component remains bound to tumor antigens, continuously presenting the IL-2 in proximity to tumor cells, thereby maintaining a persistent therapeutic effect that reduces dosing frequency compared to systemic administration
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The polypeptide constructs effectively enhance IL-2 signaling in PD-1+ cells, promoting anti-tumor responses without the need for systemic IL-2 administration, thereby reducing toxic side effects and improving treatment efficacy.
Implementation Method 1
the targeting moiety binds to PD-1, NKG2a, CD8a, FcRL6, CRTAM or LAG3
Implementation Method 2
a CD25 moiety... the CD25 moiety is fused to the C-terminus of one of the heavy chains of an anti-PD1 antibody
Data Source
AI summary
The present disclosure provides constructs comprising an anti-PDI antibody, or an alternative targeting moiety, fused to CD25 or an IL-2 binding fragment of CD25. Such constructs find use in treating human diseases, such as cancer.