ABSTRACT
PURPOSE: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates. EXPERIMENTAL DESIGN: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates. RESULTS: In a murine melanoma tumor model, the ratio of tumor-killing CD8(+) T cells to Foxp3(+) regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti-CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates. CONCLUSIONS: These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies.
Subject(s)
Antineoplastic Agents/pharmacology , Interleukin-2/analogs & derivatives , Neoplasms/metabolism , Neoplasms/pathology , Polyethylene Glycols/pharmacology , Prodrugs , Receptors, Interleukin-2/metabolism , Recombinant Fusion Proteins/pharmacology , Animals , Antineoplastic Agents/chemistry , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CTLA-4 Antigen/antagonists & inhibitors , Cell Line, Tumor , Disease Models, Animal , Drug Synergism , Female , Humans , Immunologic Memory , Interleukin-2/chemistry , Interleukin-2/pharmacology , Lymphocytes, Tumor-Infiltrating , Male , Melanoma, Experimental , Mice , Models, Molecular , Molecular Conformation , Neoplasms/drug therapy , Neoplasms/immunology , Polyethylene Glycols/chemistry , Protein Binding , Receptors, Interleukin-2/chemistry , Recombinant Fusion Proteins/chemistry , Recombinant Proteins/pharmacology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Tumor Burden/drug effectsABSTRACT
BACKGROUND: CKD-602, a topoisomerase I inhibitor, has antitumor activity in a broad spectrum of tumor types. STEALTH liposomal CKD-602 (S-CKD602) prolongs circulation of CKD-602 in plasma, increases drug exposure in tumors and improves efficacy compared with free drug. MATERIALS AND METHODS: Different dosing regimens of S-CKD602, free CKD-602 and topotecan were compared for antitumor activity in female athymic nude mice bearing human A375 melanoma, ES-2 ovarian, H82 SCLC or HT-29 colon tumor xenografts. RESULTS: S-CKD602 was more efficacious than free drug in all tumor types studied. The therapeutic index (TI) of S-CKD602 was estimated to be approximately 6-fold greater than that of free CKD-602 in ES-2 and approximately 3-fold greater in H82 tumors. TI of S-CKD602 was approximately 2-fold greater than that of free CKD-602 and approximately 5-fold greater than that of topotecan in A375, and > or = 3-fold greater in HT-29 tumors. In A375 tumors, once-weekly dosing of S-CKD602 was superior to once every 2 weeks or twice weekly schedules. CONCLUSION: The therapeutic index of S-CKD602 was greater than that of free CKD-602 and topotecan in several human tumor types.
