Bispecific Antibodies Modulating IL-2 Receptor Binding Specificity
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Solution Overview
Problem
High doses of IL-2 therapy for treating certain diseases are toxic due to adverse effects like vascular leak syndrome, and there is no effective treatment for this condition, which is caused by the release of proinflammatory cytokines from IL-2-activated NK cells and direct binding of IL-2 to lung endothelial cells.
Innovation Solution
Development of bispecific antibodies or antigen binding fragments that specifically bind to CD122 and common γ chain (γc), acting as IL-2 receptor agonists to stimulate immune cells without activating high-affinity IL-2R α-β-γc receptors, thereby reducing toxicity and promoting immune stimulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If high doses of IL-2 are administered for effective treatment, then immune stimulation is improved, but vascular leak syndrome and pulmonary edema occur due to direct binding to lung endothelial cells
Solution Approach 1:
The patent employs blocking antibodies against IL-2Rα as intermediaries to prevent direct binding of IL-2 to lung endothelial cells. The antibody complex acts as a mediator that allows IL-2 to stimulate immune cells through intermediate-affinity receptors while blocking the harmful high-affinity interaction with endothelial cells, thereby resolving the contradiction between effective immune stimulation and avoidance of vascular leak syndrome
Solution Approach 2:
The invention applies local quality by creating differential receptor interactions: the antibody complex selectively allows binding to intermediate-affinity IL-2Rβ-γc receptors on immune cells while blocking high-affinity IL-2Rα-β-γc receptors on endothelial cells. This spatially selective binding pattern enables immune stimulation in specific tissues while preventing harmful effects in others
2Productivity
If high doses of IL-2 are administered, then immune cell activation is improved, but proinflammatory cytokine release from NK cells causes toxicity
Solution Approach 1:
The patent applies partial action by using submaximal doses of IL-2 in combination with blocking antibodies, which provides sufficient immune cell activation through intermediate-affinity receptors while avoiding the excessive activation that triggers harmful proinflammatory cytokine release. The blocking antibody modulates the response to achieve optimal activation without overstimulation
Solution Approach 2:
The blocking antibody serves as an intermediary that modulates IL-2 signaling to achieve controlled immune cell activation. It allows beneficial activation through intermediate-affinity receptors while preventing the excessive signaling that would trigger harmful cytokine release from NK cells
3Object-affected harmful factors
If IL-2Rα is blocked to prevent VLS, then pulmonary edema is reduced, but immune stimulation may be compromised
Solution Approach 1:
The invention achieves multi-functionality by using a single IL-2/antibody complex that simultaneously blocks harmful high-affinity interactions with endothelial cells while preserving beneficial intermediate-affinity interactions with immune cells. This universal approach addresses both protection from VLS and maintenance of immune stimulation through one therapeutic agent
Data Source
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AI summary
Anti-CD122 and/or yc antibodies and fragments thereof are disclosed. Also disclosed are compositions comprising such antibodies and fragments, and uses and methods using the same.