Bempegaldesleukin (NKTR-214): a CD-122-biased IL-2 receptor agonist for cancer immunotherapy

Figures & data

Figure 1. Model demonstrating region of PEGylation sites at IL-2 interface with IL-2Rα. Bempegaldesleukin is aldesleukin at its core (green) bound through surface lysines to six PEG chains per molecule as determined by reverse-phase HPLC quantification of completely released PEG and protein (eight replicates for four lots of bempegaldesleukin). Sites of PEGylation are depicted by red circles. The γ_c receptor is depicted in pink, IL-2Rβ in aqua blue, and IL-2Rα in dark blue. Only peptide 68–94 (VLNLAQSK75NFHLRPRDLISNINVIVLE) and peptide 20–51 (LQMILNGINNYK31NPK34LTRMLTFK42FYMPK47K48ATE) were bound by PEG. The PEGylation results represent six separate experiments, each with two replicates, using three batches of bempegaldesleukin.

Adapted from Wang [16]. Reproduced with permission from AAAS.

Figure 2. Bempegaldesleukin is a CD122-preferential cytokine agonist conjugated with multiple releasable chains of PEG located at the interface of IL-2 and IL-2Rαβγ. The PEG chains slowly release at physiological pH, creating conjugated-IL-2 species with fewer PEG chains and increased bioactivity.

Reproduced with permission from Charych D, et al. PLoS One. 2017;12(7):5451–5458 [21]

Table 1. Ongoing bempegaldesleukin combination clinical trials.

Phase	Combination Agent	Tumor Type	Clinicaltrials.gov
Phase 3	Nivolumab	Melanoma	NCT03635983
Phase 3	Nivolumab	RCC	NCT03729245
Phase 2 (PIVOT-10)	Nivolumab	Urothelial	NCT03785925
Phase 1/2 PIVOT-02	Nivolumab	5 tumor types and 13 indications, including first- and second-line melanoma, first- and second-line RCC, first- and second-line NSCLC, first- and third-line urothelial carcinoma, and first- and second-line TNBC	NCT02983045
Phase 1/2 PROPEL	Atezolizumab or pembrolizumab	Urothelial bladder cancer, melanoma, NSCLC	NCT03138889
Phase 1/2 REVEAL	NKTR-262 (a novel small-molecule agonist of TLR 7/8 administered as an intratumoral injection) [26]	Melanoma, Merkel cell carcinoma, TNBC, RCC, colorectal cancer, SCCHN, sarcoma	NCT03435640
Phase 1b/2	Avelumab (an anti-PD-L1 antibody) and talazoparib (a PARP inhibitor) or enzalutamide (an androgen receptor inhibitor)	SCCHN and mCRPC	NCT04052204

mCRPC, metastatic castration-resistant prostate cancer; NSCLC, non-small cell lung cancer; PARP, poly (ADP-ribose) polymerase; PD-L1, programmed death-ligand 1; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; TLR, toll-like receptor; TNBC, triple negative breast cancer.

Wang X, Rickert M, Garcia KC. Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science. 2005;310(5751):1159–1163.

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Charych D, Khalili S, Dixit V, et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One. 2017;12(7):5451–5458.

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Diab A, Marcondes M, Cattaruzza F, et al. Phase 1b: preliminary clinical activity and immune activation for NKTR-262 [TLR 7/8 agonist] plus bempegaldesleukin (NKTR-214) [CD122-biased agonist] in patients (pts) with locally advanced or metastatic solid tumors (REVEAL phase 1b/2 trial). Presented at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; 2019 March 1; San Francisco.

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