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Preclinical studies on targeted delivery of multiple IFN?2b to HLA-DR in diverse hematologic cancers.

ABSTRACT: The short circulating half-life and side effects of IFN? affect its dosing schedule and efficacy. Fusion of IFN? to a tumor-targeting mAb (mAb-IFN?) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFN? comprising tetrameric IFN?2b site-specifically linked to hL243 (humanized anti-HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFN? or a mixture comprising the parental mAb and IFN?. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFN? and hL243. C2-2b-2b induced more potent and longer-lasting IFN? signaling compared with nontargeted IFN?. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis. C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFN?, peginterferonalfa-2a, or a combination of hL243 and IFN?, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies.

SUBMITTER: Rossi EA

PROVIDER: S-EPMC3158718 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers.

Rossi Edmund A EA Rossi Diane L DL Cardillo Thomas M TM Stein Rhona R Goldenberg David M DM Chang Chien-Hsing CH

Blood 20110616 7

The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting mAb (mAb-IFNα) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFNα comprising tetrameric IFNα2b site-specifically linked to hL243 (humanized anti-HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this ...[more]

PMID: 21680794

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Project description:BackgroundTo investigate the changes of human leukocyte antigen DR (HLA-DR) and CD38 coexpression subsets on T lymphocytes following interferon (IFN) therapy for those who have chronic hepatitis B (CHB).MethodsA prospective cohort of CHB patients participated in this study. CHB patients without IFN treatment (including naïve and nucleoside [nucleotide] analogs [NAs]-treated patients) were given pegylated interferon alfa (Peg-IFNα) treatment. Peripheral blood samples were taken at baseline, 4 weeks and 12-24 weeks of Peg-IFNα treatment. For the patients who entered the Peg-IFNα plateau phase due to the stagnation of the decrease in HBsAg, and Peg-IFNα was discontinued and Peg-IFNα therapy was resumed after an interval of 12-24 weeks. During the interval, they received first-line NAs treatment. Peripheral blood samples were collected at the baseline of the plateau phase, 12-24 weeks of intermittent treatment, and 12-24 weeks of Peg-IFNα retreatment. The peripheral blood samples were taken to determine virological, serological and biochemical indices of hepatitis B virus (HBV), and T lymphocyte related phenotypes were detected using flow cytometry.ResultsIn the process of long-term treatment of Peg-IFNα, the percentage of HLA-DR+CD38dim subsets increased significantly at first, then decreased gradually, while the percentage of HLA-DR+CD38hi subsets markedly increased. During long-term Peg-IFNα treatment, there was a considerable negative correlation between HBsAg and the HLA-DR+CD38hi subset percentage. The persistent high proportion of HLA-DR+CD38hi subsets was related to the occurrence of Peg-IFNα plateau phase. After Peg-IFNα intermittent treatment, the percentage of HLA-DR+CD38hi subsets decreased significantly. After Peg-IFNα retreatment, the level of HBsAg began to decrease again. At the same time, the percentage of HLA-DR+CD38hi subsets significantly increased, but it was still lower than that at the baseline level.ConclusionsThe spectrum of HLA-DR and CD38 coexpression subsets on T lymphocytes changed during the long-term treatment of IFN. The establishment of the IFN plateau phase was linked to the persistence of a considerable proportion of HLA-DR+CD38hi subsets on T lymphocytes. IFN intermittent treatment could significantly reduce the proportion of HLA-DR+CD38hi subsets, helping regain the antiviral efficacy of IFN during IFN retreatment.

Dataset Information

Preclinical studies on targeted delivery of multiple IFN?2b to HLA-DR in diverse hematologic cancers.

Publications

Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers.

Similar Datasets

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