Abstract P198: MDNA11 is a long-acting ‘beta-only’ IL-2 agonist that demonstrates a safe and durable anti-tumor immune response

• Published in: Molecular cancer therapeutics 2021-12, Vol.20 (12_Supplement), p.P198-P198
• Main Authors: To, Minh D., Merchant, Fahar, Muhsin, Ma'an, Galligan, Carole, Pearce, L. Bruce, Lloyd, Peter, Merchant, Rosemina
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-21-P198

Background: MDNA11 is an engineered ‘beta-only’ IL-2 superkine with (1) enhanced affinity for IL-2Rb (CD122) to preferentially activate anti-cancer effector immune cells and (2) extended half-life by fusion to human albumin, avoiding the need for frequent administration. Methodology: MDNA11 was characterized in in vitro and in vivo studies including assessment of efficacy in syngeneic tumor models as single agent and in combination with immune checkpoint inhibitors (CPIs). A GLP study in non-human primate was conducted to evaluate the safety, pharmacodynamic and pharmacokinetic profiles of MDNA11. Results: MDNA11 does not bind IL-2Ra (CD25) but demonstrates a 30-fold higher affinity for IL-2Rb (CD122), resulting in enhanced in vitro STAT5 signaling in human NK and CD8+ T-cells with diminished activation in Tregs when compared to rhIL-2. In CT26 and MC38 syngeneic tumor models, MDNA11 demonstrated potent and durable anti-tumor activity as monotherapy (Q1W x 2) and synergized with anti-PD1 and anti-CTLA4 to achieve complete response and tumor clearance. These mice were protected against relapse and subsequent tumor re-challenges without any further treatment by inducing long-term antigen-specific CD8+ T-cells. MDNA11 binds to human and cynomolgus monkey IL-2 receptors with near-identical affinity. A GLP toxicology study involving intravenous administration on a Q2W x 3 schedule showed that MDNA11 was well tolerated up to the highest planned dose of 600 mcg/kg. The most common clinical observations were dehydration and diarrhea, which generally occurred following the first but not subsequent dose administration. There was a dose-proportional increase in Cmax and AUC. MDNA11 induced dose-dependent proliferation and expansion of peripheral CD4+ and CD8+ T-cells lasting beyond 7-days following each administration. Similar stimulatory effects on NK cells were observed but effects on Tregs were limited. Despite the robust immune response, there was no sign of cytokine release syndrome nor evidence of ADA. At the highest dose of MDNA11 (600 mcg/kg), an increase in eosinophil counts was observed following the second dose, but histopathological evaluation showed no evidence of pulmonary edema nor vascular leak syndrome in all organs examined. These data constitute a strong framework for the conduct of a phase 1/2 study in patients with advanced solid tumors that encompasses dose escalation, dose expansion, and combination with CPIs. Conclusions: MDNA11 is a long-acti