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.
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