Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies
IL-2 and IL-15 agonists have been approved as cancer therapies. However, their clinical application has been impeded by systemic toxicities. We demonstrated that IL-2R/IL-15R signaling can be selectively activated within the tumor, thereby minimizing associated systemic toxicities, by utilizing a bsAb pair consisting of IL-2Rβxtumor associated antigen (TAA) and Il-2RγxTAA bsAbs. This approach has demonstrated significant promise, including:
✅ Selective IL-2R/IL-15R signaling activation only in the presence of TAA+ tumor cells
✅ Selective intra-tumor activation and proliferation of NK and central memory CD8+ T cells
✅ Lack of peripheral activation and toxicities associated with systemic IL-2 therapy
✅ Synergetic anti-tumor activity in combination with checkpoint inhibitors
The strategy provides a safe manner to harness the anti-tumor potential of IL-2/IL-15 signaling pathways. Our NI-3501 project based on this strategy is now in preclinical development to treat solid tumors.
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