M40403 and IL-2 Induced Hypotension

描述（由申请人提供）：淋巴因子白细胞介素2（IL-2）是 目前已被FDA批准用于治疗转移性肾细胞癌 和恶性黑素瘤。IL-2的临床应用受到其严重的局限性。 副作用，尤其是低血压。由于这种剂量限制的一面， 由于IL-2的作用，IL-2给药的整个周期经常被缩短。我们发现 M40403，MetaPhores原型超氧化物歧化酶模拟物（SODm） 完全减弱IL-2诱导的低血压，并允许IL-2的剂量为 从180，000 IU升至400，000 IU。M40403不干扰 IL-2的抗肿瘤作用。相反，M40403增加了IL-2介导的 淋巴因子激活的杀伤细胞的激活，如体外 在体内实验中，与IL-2的抗肿瘤作用协同， 体内肿瘤模型。这些初步结果表明，M40403抑制了 IL-2给药的剂量限制性毒性，而不干扰其 抗肿瘤作用事实上，我们的数据表明， IL-2的作用。因此，需要对M40403进行临床评价，因为1）它 逆转IL-2诱导的低血压; 2）增加IL-2诱导的抗癌作用 3）具有直接的抗癌活性。根据初步数据 如上所述，MetaPhore的目标是完成临床前评估 M40403的剂量限制&测试该试剂减弱剂量限制的能力 在临床试验中IL-2的毒性（低血压）。如果初步数据是 通过第一阶段申请中提出的工作确认，我们希望 积极地进入第二阶段的开发工作， 候选人进行临床试验。 拟议商业应用：不可用

DESCRIPTION (provided by applicant): The lymphokine interleukin 2 (IL-2) is currently approved by the FDA as therapy for metastatic renal cell carcinoma and malignant melanoma. The clinical use of IL-2 has been limited by its severe side effects, particularly hypotension. Because of such dose-limiting side effects, the full period of IL-2 dosing is frequently curtailed. We have found that M40403, MetaPhores prototypic superoxide dismutase mimetic (SODm) completely attenuated IL-2 induced hypotension & allowed the dose of IL-2 to be escalated from 180,000IU to 400,000IU. M40403 did not interfere with the anti-tumor effects of IL-2. In contrast, M40403 increased IL-2 mediated activation of the lymphokine activated killer cells as demonstrated by in vitro & in vivo experiments & synergized with the anti-tumor effects of IL-2 in in vivo tumor models. These preliminary results suggest that M40403 inhibits the dose limiting toxicity of IL-2 administration without interfering with its antitumor effects. In fact, our data suggests a potentiation of the anti-tumor effects of IL-2. Thus, clinical evaluation of M40403 is warranted because 1) it reverses IL-2 induced hypotension 2) it increases IL-2 induced anti-cancer responses & 3) it has a direct anti-cancer activity. Based on preliminary data summarized above, MetaPhore's goals are to complete the preclinical evaluation of M40403 & to test the capacity of this agent to attenuate the dose limiting toxicity (hypotension) of IL-2 in a clinical trial. If the preliminary data is confirmed by the work proposed in this Phase I application, we would expect to follow aggressively into a Phase II development effort to move this drug candidate forward to clinical trials. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE