Abstract B118: Potentiation of IL-2’s antitumor efficacy without compromised tolerability by a novel human antibody

Abstract

Abstract IL-2 was the first approved cancer immunotherapy and is still recognized for its durable responses. While IL-2 does mobilize relevant antitumor immune cells such as CD8+ T effector and activated NK cells, its utility is limited by parallel expansion of Treg cells and by dose-limiting toxicities. IL-2 Receptor alpha chain binding by IL-2 may be important in driving Treg expansion and some adverse side effects. Over the last decade, there have been approaches at modifying IL-2 structure-function or selecting antibodies that bind IL-2 and bias its activation of preferential cell types. One candidate (pegylated IL-2, NKTR-214) has moved into clinical development. XOMA mAb19 is a fully human monoclonal antibody to IL-2 that selectively compromises binding to IL-2R alpha chains, but not beta-gamma chains, thus potentially expanding IL-2’s antitumor therapeutic index. mAb19 binding characteristics and efficacy in a mouse Lewis Lung Carcinoma model were described at SITC 2016. In the current studies, a CT26 mouse colon carcinoma model was utilized to assess antitumor efficacy and tolerability of combined mAb19 + low-dose IL-2 dosing and to compare such with standard high-dose IL-2 regimens. The CT26 study results presented here demonstrate that mAb19 and IL-2 coadministration potentiates IL-2’s antitumor activity, expands CD8+ T effector and activated NK cells but not Treg cells, and is well tolerated. Specifically, treatment of tumor-bearing mice with about 1 mg/kg mAb19 plus about 0.1 mg/kg IL-2 yielded significant antitumor efficacy, which was at least as substantial as high-dose (e.g. 5 mg/kg) IL-2 regimens wherein significant body weight loss and ~10% mortality were observed. Notably, the mAb19 + IL-2 regimen had no dose-limiting toxicity. Moreover, the magnitude of antitumor response of the combination mAb19+IL2 was superior to that reported for NKTR-214 in the same model (AACR 2015). Preclinical development continues, including assessment for enhanced efficacy with checkpoint inhibitor(s). Citation Format: Kirk Johnson, Ou Li, Xiaohe Liu, Lucia Beviglia. Potentiation of IL-2’s antitumor efficacy without compromised tolerability by a novel human antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B118.