Bempegaldesleukin (development code NKTR-214) is an

experimental An experiment is a procedure carried out to support or refute a hypothesis, or determine the efficacy or likelihood of something previously untried. Experiments provide insight into cause-and-effect by demonstrating what outcome occurs when a ...

anti-cancer drug candidate. It is a

PEGylated PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein ...

interleukin-2 Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible fo ...

(IL-2) acting as a

CD122 Interleukin-2 receptor subunit beta is a protein that in humans is encoded by the ''IL2RB'' gene. Also known as CD122; IL15RB; P70-75. Function The interleukin 2 receptor, which is involved in T cell-mediated immune responses, is present in 3 ...

-preferential IL-2 pathway agonist designed to activate and proliferate CD8⁺ T cells and

NK cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

. It is being developed by

Nektar Therapeutics Nektar Therapeutics (Nektar) is an American biopharmaceutical company. The company was founded in 1990 and is based in San Francisco, California. The company develops new drug candidates by applying its proprietary PEGylation and advanced polymer ...

. In August 2019 the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

granted

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...

designation to bempegaldesleukin in combination with

nivolumab Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urotheli ...

for the treatment of advanced melanoma. It is in phase 3 clinical trials for melanoma and

renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cance ...

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Mechanism of action

Bempegaldesleukin is a recombinant form of human cytokine

conjugated to six releasable polyethylene glycol chains.

PEGylation PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein ...

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 The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosu ...

(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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the 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

within the tumor microenvironment without expanding the undesirable intra-tumoral regulatory T cells.

Development

Bempegaldesleukin is investigated in combination with other anti-cancer agents. In February 2018

announced development and commercialization collaboration with

Bristol-Myers Squibb The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...

to evaluate combination of bempegaldesleukin and

. In November 2018 Nektar announced collaboration with

Pfizer Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...

to evaluate combination of Bempegaldesleukin with

avelumab Avelumab, sold under the brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma. Common side effects include fatigue, musculoskeletal pain, ...

and talazoparib or

enzalutamide Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castrat ...

in multiple cancers. In March 2022 it was reported that trials for melanoma didn't meet statistical significance at the first interim analysis.

References

{{Reflist Experimental cancer drugs