RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Interleucina-2/análogos & derivados , Neoplasias/metabolismo , Neoplasias/patologia , Polietilenoglicóis/farmacologia , Pró-Fármacos , Receptores de Interleucina-2/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Animais , Antineoplásicos/química , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Memória Imunológica , Interleucina-2/química , Interleucina-2/farmacologia , Linfócitos do Interstício Tumoral , Masculino , Melanoma Experimental , Camundongos , Modelos Moleculares , Conformação Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Polietilenoglicóis/química , Ligação Proteica , Receptores de Interleucina-2/química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
AIM: To evaluate the antifertility activity of Artemisia vulgaris leaves on female Wistar rats. METHOD: The plant extract was tested for its effect on implant formation at two dose levels, 300 and 600 mg·kg⻹, respectively. The effective methanolic plant extract was further studied for estrogenic potency on ovariectomised immature female Wistar rats. RESULTS: The data presented in this study demonstrate the antifertility potential of Artemisia vulgaris methanolic leaf extract, which shows a strong and significant decrease in implant formation (100%), and a strong estrogenic effect resulting in a significant increase in uterine weight in immature ovariectomised rats. These observations suggest that the methanolic extract of Artemisia vulgaris leaves has strong anti-implantation activity and estrogenic activity. CONCLUSION: The methanolic plant extract of A. vulgaris has antifertility activity.
