717 Selective activation of CD8+ T cells by a CD8-targeted IL-2 results in enhanced anti-tumor efficacy and safety

• DOI: 10.1136/jitc-2021-sitc2021.717
• Publication Date: 2021-11-09T15:30:04Z
• Authors: Kelly Moynihan; Danielle Pappas; Terrence Park; Wei Chen; Irene Ni; Paul Bessette; Mike Chin; Ton Schumacher; Andy Yeung; Ivana Djuretic
• Keywords: Interleukin 15

<h3>Background</h3> High-dose IL-2 induces complete responses in a subset of cancer patients, but severe toxicity, including vascular leak syndrome (VLS), limits its clinical potential. Insights into IL2Rα9s role the development VLS sparked wave second-generation molecules referred to as "not-α" IL-2s. Emerging data suggests that although not-α IL-2s avoid VLS, they induce suboptimal monotherapy activity patients. Given observation CD8+ T cells are dominant effector with IL-2-based therapies,^{1 2} we hypothesized maximizing on T-cells and limiting immunosuppressive Tregs highly IL-2-sensitive innate populations would improve IL-29s efficacy tolerability. We developed cis-targeted (CD8-IL2) fusion proteins selectively activate have minimal CD8-negative cells. <h3>Methods</h3> In vitro selectivity CD8-IL2 was tested primary immune mouse splenocytes human PBMCs. vivo evaluated syngeneic tumor models non-human primates. <h3>Results</h3> Due 10–20x higher expression IL2Rβ NK over other lymphocytes, induced preferential cell expansion mice. Toxicity-induced body weight loss treatment dependent expressing NK1.1 not CD8. To overt activation IL2Rβhigh cells, IL-2Rα-associated Treg activation, generated consisting anti-CD8 antibodies muteins attenuated binding IL2Rα IL2Rβ. demonstrated fusions preferentially activated within mouse, human, cynomolgus populations, 100–1000 fold for all three species. Selective peripheral blood compartments also monkeys. Furthermore, single dose mice elicited strong MC38 tumors, majority demonstrating without detectable at doses were well tolerated contrast, alpha &gt;10% prior reaching efficacious did drive any anti-tumor responses. <h3>Conclusions</h3> CD8-targeted has superior lower toxicity compared IL-2. Development AB248, novel molecule is underway. <h3>References</h3> Rakhmilevich A, North R. Elimination CD4+ bearing an advanced sarcoma augments antitumor action interleukin-2. <i>Cancer Immunol Immunother</i> 1994;<b>38</b>(2):107–12. Sun Z, Ren Z. A next-generation tumor-targeting promotes tumor-infiltrating T-cell response effective control. <i>Nat Commun</i> 2019;<b>3874</b>:1–12.