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Oct 27, 2016
 |  BC Innovations  |  Targets & Mechanisms

Cancer’s Phoenix

A safer IL-2-based immunotherapy without compromised efficacy

Although recombinant IL-2 was a cancer immunotherapy long before checkpoint inhibitors came on the scene, the cytokine’s impact was limited by its potential for lethal side effects. Most attempts to lower toxicity also decreased efficacy. Now, a Washington University in St. Louis team has presented a strategy that not only avoids the adverse events but boosts efficacy, and has spun out Courier Therapeutics Inc. to take it to the clinic.

Company founder Alexander Krupnick, who led the study while at Wash U, told BioCentury that while the cancer immunotherapy field has largely abandoned IL-2, with only a handful of companies still trying to tweak the protein, he thinks the approach still holds promise. Krupnick is now an associate professor of surgery at University of Virginia.

Novartis AG pioneered recombinant IL-2 with Proleukin aldesleukin, which was approved in 1992 for renal cell carcinoma (RCC) and in 1998 for metastatic melanoma.

According to Krupnick, Proleukin produced complete response rates that were comparable to the anti-PD-1 therapies Opdivo nivolumab from Bristol-Myers Squibb Co. and Keytruda pembrolizumab from Merck & Co. Inc., but the remissions lasted considerably longer (see “Check This Out,” page 3).

Figure: Check This Out

Therapeutic response rates for metastatic renal cell carcinoma (RCC) patients treated with high-dose IL-2 or anti-PD1 antibody therapies, broken down by complete response (CR), partial response (PR) and no response (NR). The chart shows data published in 1998 for Proleukin aldesleukin, a recombinant IL-2 marketed by Novartis AG (NYSE:NVS; SIX:NOVN), in 227 patients, and data published in 2015 for Opdivo nivolumab, an anti-PD-1 antibody from Bristol-Myers Squibb Co. (NYSE:BMY) and Ono Pharmaceutical Co. Ltd. (Tokyo:4528), in 821 patients. Source: Courier Therapeutics Inc.; Motzer, R., et al. “Nivolumab versus everolimus in advanced renal-cell carcinoma.” New England Journal of Medicine (2015); Rosenberg, S., et al. “Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin 2: Identification of the antigens mediating the response.” Annals of Surgery (1998).

Figure: Aim intermediate

To avoid dose-limiting toxicities associated with recombinant IL-2, researchers at Washington University in St. Louis have created a fusion protein that directly targets a mutant version of the cytokine (mutIL-2) to cytotoxic lymphocytes.

Top Panel: OMCP-mutIL-2 contains a 133-amino acid mutant IL-2 protein (mutIL-2) that has two amino acid substitutions, R38A and F42K (*), linked to the 152-amino acid cowpox virus protein orthopoxvirus major histocompatibility complex class I-like protein (OMCP). The two substitutions eliminate binding to CD25, a subunit present only in the high affinity IL-2 receptor which is responsible...

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