On April 8, 2022 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported the presentation of new data from its preclinical-stage IL-18 and LAG3-targeted IL-15 cytokine programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, Xencor, APR 8, 2022, View Source [SID1234611684]).

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"XmAb cytokines are engineered to be long acting and more drug-like in order to overcome inherent limitations facing cytokine therapeutics. At AACR (Free AACR Whitepaper), we are presenting two additions to our wholly owned cytokine portfolio — a decoy-resistant and potency-reduced IL18-Fc fusion protein, and a LAG-3 targeted IL15/IL15Rα-Fc fusion protein, which is biased toward binding and activating LAG-3-positive lymphocytes that are more likely to be tumor-reactive," said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. "Later this year we plan to submit an investigational new drug application for XmAb662, our wholly owned, reduced-potency IL12-Fc cytokine, which has demonstrated remarkable preclinical anti-tumor activity and improved therapeutic index in vivo."

The posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

Abstract 2080, "LAG3-targeted IL15/IL15Rα-Fc (LAG3 x IL15) fusion proteins for preferential TIL expansion"

Session: Immunomodulatory Agents and Interventions 1
Date and Time: Monday, April 11, 2022, 1:30 – 5:00 p.m. CDT
Location: Exhibit Halls D-H, Section 38, Board 18
IL-2 and IL-15 are cytokines that cause the activation and proliferation of T cells and NK cells. Their therapeutic potential has been well established in preclinical models and clinical studies; however, when given systemically, these potent cytokines have historically provided a poor therapeutic window, as they are not well tolerated and are quickly cleared from circulation.

Xencor engineered LAG3-targeted IL15/IL15Rα-Fc cytokine/antibody fusion proteins (LAG-3 x IL-15) for selective activation of LAG3-positive immune cells, which may potentially avoid systemic toxicities arising from off-target activation and expansion of peripheral immune cells. An XmAb heterodimeric Fc domain serves as a molecular scaffold, and Xtend technology promotes longer circulating half-life. LAG-3 is an immune checkpoint expressed on tumor-infiltrating lymphocytes (TILs), is frequently co-expressed with PD-1 and has limited expression in normal peripheral immune cells. Recently, anti-LAG3 agents have generated promising results in clinical studies, and LAG-3 x IL-15 agents could be combined with anti-PD1 agents. Xencor’s LAG-3 x IL-15 candidate molecules demonstrated high selectivity for LAG3-positive cell populations in multiple in vitro and in vivo models.

Abstract 3515, "Engineered IL18 heterodimeric Fc-fusions featuring improved stability, reduced potency, and insensitivity to IL18BP"

Session: Immunomodulatory Agents and Interventions 2
Date and Time: Tuesday, April 12, 2022, 1:30 – 5:00 p.m. CDT
Location: Exhibit Halls D-H, Section 37, Board 17
IL-18 is a proinflammatory cytokine that modulates both the innate and adaptive immune responses. IL-18 receptor 1, the primary co-receptor for IL-18, is overexpressed on activated T cells and NK cells, which are critical for anti-tumor responses. Additional preclinical studies of IL-18 have demonstrated its anti-tumor activity, including synergy with immune checkpoint inhibitors and CAR-T therapies. In contrast with other potent cytokines, IL-18 has been well tolerated in clinical trials but demonstrated a lack of efficacy despite heavy dosing. IL-18 participates in a negative feedback loop with a high affinity natural inhibitor, IL18BP, which was observed to be upregulated in early phase clinical studies and may have directly resulted in IL-18’s limited clinical performance.

Xencor engineered stabilized, potency-reduced, monovalent IL-18 cytokines fused to an XmAb heterodimeric Fc domain with Xtend Fc technology for longer half-life. Importantly, these cytokine-Fc fusions were engineered to not bind its inhibitor, IL18BP. In a preclinical mouse model of graft-versus-host disease, an analog of the candidate XmAb143 led to the expansion and proliferation of target immune cells and induced high levels of interferon gamma. Further, it was well tolerated in non-human primates and exhibited favorable pharmacokinetics, such as slow receptor-mediated clearance.