Abstract 2120: A novel engineered IL-21-based immunocytokine as a therapeutic approach for tumor targeting in renal cancer

RCC is a lethal disease whose incidence is on the rise. Clear cell renal cell cancer (ccRCC), the most aggressive and the deadliest variant of this cancer, accounts for ∼ 85% of all RCC cases. In the past decade, the landscape of immunotherapeutic approaches with the focus on use of cytokines for advanced ccRCC has expanded rapidly. The therapeutic potential of IL-21 as a novel treatment option for patients with advanced ccRCC has been evaluated in phase 1 and 2 clinical trials. Despite promising anti-tumor effects, severe dose-limiting toxicities of systemic administration of IL-21 were frequently reported in clinical trials. CD70, a TNF-ligand family member, is transiently expressed and restricted to a subset of highly activated T, B, and dendritic cells, but is highly overexpressed in all ccRCC tumors. In RCC, tumor-expressed CD70 results in exhaustion of immune cells, thereby promoting immune escape. Therefore, targeting CD70 has been thought to be promising therapeutic strategy for RCC. Thus, a variety of CD70-targeting approaches, focused on antibody dependent cellular cytotoxicity (ADCC) or antibody-drug conjugates, have been evaluated in multiple trials. Despite some studies demonstrated limited response rate, frequently related to dose-limiting off-target cytotoxicity, the successes indicated generation of an effective immune response toward RCC. To achieve our goals aiming to take an advantage to combine the benefits of anti-CD70 therapy with tumor restricted targeting of IL21, we have designed and generated for the first time a novel humanized anti-CD70-IL-21 fusion antibody. This fusion antibody simultaneously binds CD70, a ligand that is highly over-expressed in ccRCC, and induces IL-21 receptor (IL-21R) mediated downstream signaling. We also disrupted heparin binding activity by site-directed mutagenesis of IL-21 portion of the immunocytokine. This resulted in significant improvement of target specificity, PK/PD properties, and ADCC-inducing activity of the immunocytokine. Importantly, our novel immunocytokine has an advantage over existing anti-CD70 targeting approaches, as it markedly alleviates ADCC-mediated exhaustion of NK cells. Finally, our animal experiments indicate that our novel immunocytokine has a significant anti-tumor potential against ccRCC in humanized mouse model reconstituted with NK-92.CD16 cells. Taken together, our data demonstrate the superior efficacy of the novel immunocytokine against ccRCC. Furthermore, this successful immunotherapeutic approach can be expanded for the management of other CD70-positive tumors. Citation Format: Anna Rastorgueva, Nicholas A. Maskalenko, Ilia Fedorov, Ekaterina Davydova, Ashot Nazaretian, Kerry S. Campbell, Peter Makhov. A novel engineered IL-21-based immunocytokine as a therapeutic approach for tumor targeting in renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2120.