Bempegaldesleukin Explained

Inn:	bempegaldesleukin
Cas Number:	1939126-74-5
Unii:	BNO1JG5MZC
Kegg:	D11669
Drugbank:	DB15140

Bempegaldesleukin (development code NKTR-214) is an experimental anti-cancer drug candidate. It is a PEGylated interleukin-2 (IL-2) acting as a CD122-preferential IL-2 pathway agonist designed to activate and proliferate CD8⁺ T cells and NK cells.^{[1] [2]} It is being developed by Nektar Therapeutics.

In August 2019 the FDA granted breakthrough therapy designation to bempegaldesleukin in combination with nivolumab for the treatment of advanced melanoma.^[3] It is in phase 3 clinical trials for melanoma and renal cell carcinoma.

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Mechanism of action

Bempegaldesleukin is a recombinant form of human cytokine interleukin-2 conjugated to six releasable polyethylene glycol chains. PEGylation of IL-2 is utilized to alter its receptor binding. PEG chains are located at the region of IL-2 that binds to the IL2Rα subunit of the heterotrimeric IL2Rαβγ complex, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ (CD122), the receptor complex predominant on CD8⁺ T cells. When fully PEGylated, it is a pro-drug that has essentially no biological activity. Upon intravenous administration, the PEG chains slowly release to generate active cytokine species. Consequently, it increases the proliferation, activation, and effector function of CD8⁺ T cells and NK cells within the tumor microenvironment without expanding the undesirable intra-tumoral regulatory T cells.^[4]

Development

Bempegaldesleukin is investigated in combination with other anti-cancer agents. In February 2018 Nektar Therapeutics announced development and commercialization collaboration with Bristol-Myers Squibb to evaluate combination of bempegaldesleukin and nivolumab.^[5] In November 2018 Nektar announced collaboration with Pfizer to evaluate combination of Bempegaldesleukin with avelumab and talazoparib or enzalutamide in multiple cancers.^[6] In March 2022 it was reported that trials for melanoma didn't meet statistical significance at the first interim analysis.^{[7] [8]}

Notes and References

1. Ekladious I, Colson YL, Grinstaff MW . Polymer-drug conjugate therapeutics: advances, insights and prospects . Nature Reviews. Drug Discovery . 18 . 4 . 273–294 . April 2019 . 30542076 . 10.1038/s41573-018-0005-0 .
2. Web site: Nektar R&D Pipeline NKTR-214 . Nektar . 16 September 2019 . en.
3. Web site: Bempegaldesleukin Plus Nivolumab Granted Breakthrough Designation in Melanoma by the FDA . Targeted Oncology . 15 September 2019.
4. Charych D, Khalili S, Dixit V, Kirk P, Chang T, Langowski J, Rubas W, Doberstein SK, Eldon M, Hoch U, Zalevsky J . 6 . Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy . PLOS One . 12 . 7 . e0179431 . 5 July 2017 . 28678791 . 10.1371/journal.pone.0179431 . free . 5497954 .
5. Web site: Bristol-Myers Squibb and Nektar Therapeutics Announce Global Development & Commercialization Collaboration for Nektar’s CD122-biased Agonist, NKTR-214 . BMS Newsroom . Bristol-Myers Squibb . 16 September 2019.
6. Web site: New Clinical Oncology Collaboration Between Nektar and Pfizer to Evaluate Combination of NKTR-214, a CD122-Biased Agonist, with Avelumab and Talazoparib or Enzalutamide in Multiple Cancers . Nektar Therapeutics . 16 September 2019 . en.
7. Web site: 2022-03-14 . Bristol Myers Squibb and Nektar Announce Update on Phase 3 PIVOT IO-001 Trial Evaluating Bempegaldesleukin (BEMPEG) in Combination with Opdivo (nivolumab) in Previously Untreated Unresectable or Metastatic Melanoma . 2022-03-16 . www.businesswire.com . en.
8. Web site: Nektar Reads Out. Unfortunately. . 2022-03-16 . www.science.org . en.