Pulsed Cyclic IL-2/IL-15Rβγ Agonist Dosing for Immune Activation
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Solution Overview
Problem
Current IL-2 and IL-15 therapies for cancer and infectious diseases face challenges such as limited efficacy, toxicity, and short in vivo half-life, with existing dosing regimens failing to optimally activate NK and CD8+ T cells while minimizing Treg expansion and vascular leakage syndrome.
Innovation Solution
A pulsed cyclic dosing regimen for IL-2/IL-15Rβγ agonists, where the agonist is administered consecutively for a few days followed by a treatment break, repeated multiple times, to maintain optimal activation of NK and CD8+ T cells without inducing Treg expansion or vascular leakage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If continuous dosing of IL-2/IL-15Rβγ agonist is used, then immune cell activation is maintained, but toxicity increases and Treg expansion occurs
Solution Approach 1:
The patent applies periodic pulsed cyclic dosing regimens where the IL-2/IL-15Rβγ agonist is administered for a specific number of days followed by a treatment break. This periodic administration pattern maintains immune cell activation while preventing the cumulative toxicity and Treg expansion associated with continuous dosing, as the treatment breaks allow the immune system to reset and reduce suppressive cell accumulation.
Solution Approach 2:
The continuous treatment period is segmented into discrete pulsing cycles with defined administration days and break periods. By dividing the treatment into separate dosing phases rather than continuous administration, the regimen achieves sustained immune activation through repeated pulses while limiting the duration of exposure that leads to toxicity and regulatory cell expansion.
2Productivity
If higher doses of IL-2/IL-15Rβγ agonist are administered, then efficacy increases, but vascular leakage syndrome occurs
Solution Approach 1:
The pulsed cyclic dosing regimen delivers therapeutic doses of the agonist in periodic bursts rather than continuous high-dose administration. This approach maintains efficacy by repeatedly stimulating immune cell activation while the treatment breaks between pulses prevent the sustained high-level stimulation that triggers vascular leakage syndrome, thereby decoupling efficacy from toxicity.
3Reliability
If IL-2Rα binding is included, then high-affinity receptor activation occurs, but Treg expansion is induced
Solution Approach 1:
The patent employs IL-2/IL-15Rβγ agonists that have been engineered to selectively bind to the IL-2Rβ and γc subunits while excluding binding to the IL-2Rα subunit. By extracting or removing the α-subunit binding capability from the agonist, the therapy activates the desired immune cell receptors (βγ heterotrimeric receptors) without triggering the high-affinity receptor pathway that leads to Treg expansion, thus achieving selective immune activation.
Data Source
AI summary
The present invention provides pulsed cyclic administration regimes and pulsed administration regimes for interleukin-2/interleukin-15 receptor βγ (IL-2/IL-15Rβγ) agonists for treating or managing cancer or infectious diseases in human patients. The administration regimes inter alia involve daily administration of IL-2/IL-15Rβγ agonists on 2, 3 or 4 consecutive days followed by days without administration.