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IL-2 program falls flat for Nektar and Bristol Myers Squibb

Next-generation IL-2 contenders may still harness the protein’s anti-cancer potential

by Asher Mullard, special to C&EN
April 20, 2022 | A version of this story appeared in Volume 100, Issue 14


Nektar Therapeutics and Bristol Myers Squibb have halted development of bempegaldesleukin, ending a multibillion dollar bet on interleukin-2 (IL-2) as an immuno-oncology drug. But a broad pipeline of next-generation IL-2 candidates is keeping hopes for the therapeutic approach alive.


$1.8 billion

Amount Bristol Myers Squibb paid Nektar Therapeutics to co-develop bempegaldesleukin

“[Bempegaldesleukin] was a flawed molecule, and we should not give up on IL-2 because of its rather unsurprising failure,” says Stanford University structural biologist K. Christopher Garcia, whose work helped renew interest in the protein.

Oncologists have had their eye on IL-2 for decades, ever since the discovery that this cytokine can stimulate the growth of the cancer-killing immune cells called T cells. But despite the US Food and Drug Administration’s approval of an IL-2-based drug called aldesleukin for renal cell carcinoma in 1992, IL-2’s therapeutic effect has been hard to harness. At the high doses needed to kill cancer cells it has severe side effects. At lower doses, it dampens the immune system.

Over the years, researchers have found that various subsets of immune cells express different versions of the IL-2 receptor. In 2012 Garcia and colleagues showed that it is possible to engineer IL-2 to have biased activity—activating only some subsets of these immune cells—and drug developers have been working ever since to re-capture IL-2’s cancer potential.

Researchers at Nektar hoped that pegylation would help do the trick. They stuck 6 protective polyethylene glycol (PEG) groups to aldesleukin to create a reservoir of the cytokine that only becomes active as the PEGs are cleaved. These bulky PEG groups also shifted the drug candidate’s activity profile towards a dimeric form of the IL-2 receptor that is expressed by naive T cells and NK cells, immune cells with cancer-killing potential.

After early clinical data hinted at activity, BMS placed its bet. In 2018, it paid $1.85 billion upfront, and committed up to $1.8 billion in milestone payments, to co-develop bempegaldesleukin. BMS would have received 35% of any profits.

The wager did not pay out. In March, the partners disclosed that two Phase 3 trials in melanoma had failed. Nektar’s bempegaldesleukin plus BMS’s PD-1 blocker nivolumab did not outperform nivolumab alone. More recently, they announced that late-stage trials in renal cell carcinoma and bladder cancer had also failed.

The partners have discontinued further development of the drug combination.

For analysts at the investment bank Leerink Swann, the wipeout is a reminder of the dangers of racing into Phase 3 trials too quickly.

Garcia does not see broad implications for the IL-2 pipeline, however, Bempegaldesleukin’s PEG groups are cleaved haphazardly, and the resulting mixture of drug species muddies its biological effects, he says. Bempegaldesleukin also stimulates immune cells with dimeric receptors throughout the body, rather than just in the tumor. The overall result, Garcia says, is a non-specific agent with toxicity limitations.

Next-generation contenders address these shortcomings, he contends.

Synthekine, founded by Garcia, is developing a candidate called STK-012 that aims to selectively stimulate a trimeric form of the IL-2 receptor only on antigen-activated T cells, immune cells that have been alerted to the presence of cancer markers. “These are the relevant T cells one wishes to expand,” Garcia says.

Other approaches are also in development. Bispecific candidates that activate the IL-2 receptor with one arm, and bind a protein on T cells with the other, might improve specificity. Conditionally active IL-2 drugs—masked cytokines that are laid bare by protein-cutting proteases in the tumor microenvironment—are in the works too.

“I believe someone will figure out how to best drug it,” Garcia says of IL-2.


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