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