3:25 PM
Mar 02, 2018
 |  BioCentury  |  Product Development

Clever pegylation pay off

How Nektar’s PEGs turned IL-2 into a viable immunotherapy partner for BMS

Nektar Therapeutics’ clever pegylation strategy allowed it to finesse the PK and dial down the toxicity of IL-2, turning a validated but problematic immuno-oncology mechanism into a viable candidate. The approach snagged a record-breaking deal with Bristol-Myers Squibb Co. to combine Nektar’s molecule with PD-1 inhibition, while still leaving Nektar open to develop its own combinations outside the deal.

Recombinant IL-2 was the original immuno-oncology drug. It has been on the U.S. market as Proleukin aldesleukin since 1992 and produces complete and durable responses in subsets of patients with renal cell carcinoma (RCC) or melanoma.

The drug never saw extensive use due to severe toxicities, which include life-threatening pulmonary edema, hypotension and capillary leak syndrome.

“Each time a patient takes that infusion, the immune system ravages their body,” said Nektar SVP of Research and CSO Jonathan Zalevsky. “Nowadays it’s hardly used because when physicians evaluate patients, they find most are not healthy enough to withstand a course of therapy.”

A slew of companies and academic groups have tried to make safer versions of the drug over the years, mostly by fusing it to moieties that preferentially target tumors, or that alter the cytokine’s binding behavior with its receptor (see “IL-2 Agonists”).

Nektar approached the problem by deploying a well-established chemical modification -- pegylation -- in a complex strategy that improved the cytokine’s PK, receptor selectivity and safety in one swoop.

The company also prioritized development of its pegylated IL-2 in combination with checkpoint inhibitors. Last November, Nektar became the first company to present clinical data on that combination, showing that NKTR-214 could expand the pool of patients responsive to PD-1 inhibition.

The data attracted an immuno-oncology world ever-eager to find combinations that boost the proportion of patients who respond to PD-1 inhibitors. The enthusiasm continued on March 2, when investors rewarded Nektar with a 22% gain in share price for reporting that two new responses among patients with stable disease brought the response rate in treatment-naïve RCC from 57% to 71%.

The data already had been sufficient to score a co-development deal with BMS, whose $1.85 billion of upfront cash and equity was the largest BioCentury’s BCIQ database has ever recorded for a biotech deal.

The pair will test the combination in more than 20 indications spanning nine tumor types in a series of Phase III trials slated to begin mid-year.

NKTR-214’s MOA could combine well with other immunotherapy mechanisms -- and Nektar retains rights to develop those combinations, as well as PD-1 combos in tumors and indications not specified in the BMS deal.

Table: IL-2 agonists

While Nektar Therapeutics (NASDAQ:NKTR) has used pegylation to improve IL-2’s safety, other companies have used targeting domains and engineered receptor specificity. Philogen S.p.A., Roche (SIX:ROG; OTCQX:RHHBY), Provenance Biopharmaceuticals Corp. and Alopexx Enterprises LLC have fused IL-2 to monoclonal antibodies specific for vascular or tumor cells, reducing serum exposure and increasing uptake and retention in tumors. Alkermes plc (NASDAQ:ALKS) created a circularly permuted fusion protein of IL-2 and the IL-2 receptor alpha chain (CD25) to bias selectivity against the form of the IL-2 receptor thought to mediate toxicity. Selected clinical-stage products are shown below. (A) In the Phase III study, Darleukin is being given as a component of Philogen’s Daromun, a combination therapy that also...

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