Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY/ABSTRACT Renal cell 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. While significant advances in treatment approaches have been achieved, two distinct groups of patients are at risk of death from kidney cancer: those who present with metastatic disease and those who recur following surgery. In the past decade, the landscape of immunotherapeutic approaches with the focus on use of cytokines for advanced ccRCC has expanded rapidly. Specifically, cytokines can play pivotal roles in numerous therapeutic regimens by acting on every phase of the cancer immunity cycle. The immunotherapeutic potential of cytokines has been demonstrated to show promising results to treat various cancers including ccRCC. This resulted in the growing number of clinical trials that explore cytokine-based drugs, not only as single agents, but also in combination with other drugs. Thus, 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 and resulted in one trial discontinuation, or moderate clinical efficacy in others. Therefore, future cytokine-based approaches require optimization of their pharmacokinetic profiles to increase the half-life and concentrations in the tumor microenvironment thereby minimizing their off-target systemic effects. In this exploratory R21 proposal, we outline a novel approach to treat ccRCC aiming to: (i) tumor-specific targeting of a novel engineered IL21 based immunocytokine with superior PK/PD properties; (ii) limit side- effects frequently seen with systemic IL-21 administration; and (iii) significantly reduce FcγRs-mediated off- target toxicity. We have designed and generated for the first time a novel immunocytokine, a humanized anti- CD70-IL-21 fusion antibody (Ab-IL21). This antibody simultaneously binds CD70, a ligand that is specifically expressed in ccRCC, and enhances NK cells cytotoxicity against ccRCC. Importantly, disruption of heparin binding activity by our new IL-21 protein results in significant improvement of PK/PD properties and shows markedly decreased hepatotoxicity of Ab-IL21 fusion antibody. We will focus on the design and deployment of novel, Ab-IL21 with highest affinity to IL-21R. We will also determine the most effective tumor-specific protease cleavable linker for the fusion of anti-CD70 antibody and IL-21 to fully release IL-21 and induce anti-CD70 mediated ADCC specifically within the RCC tumor microenvironment. To test our hypothesis and to validate the therapeutic value of Ab-IL21, we propose the following Specific Aims: (1) Development of the leading Ab-IL21 fusion with superior IL21 activity and target specificity; (2) To evaluate anti-tumor efficacy of Ab-IL21 in humanized mouse PDX models.
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