Mitogenic properties of a bispecific single-chain Fv-Ig fusion generated from CD2-specific mAb to distinct epitopes [In Process Citation]

The combination of anti-CD2 mAb 9.6 and 9-1, specific for distinct epitopes, induces proliferation of resting human T cells. The mitogenic activity of this mAb mixture depends upon accessory cells and the 9-1 mAb Fc domain. To further study the functional properties of these mAb, their variable regions were cloned and expressed as monospecific single- chain Fv (scFv) proteins fused to the human IgG1 Fc domain (scFvIg). A novel bispecific scFvIg was constructed by cloning the two monospecific scFv binding sites in tandem, with the 9.6 scFv placed N-terminal to the 9-1 scFvIg. Monospecific scFvIg binding to CD2 was comparable to that of the corresponding parental mAb, while the bispecific scFvIg exhibited binding activity similar to that of the 9-1 scFvIg. The combination of 9.6 scFvIg and 9-1 mAb was mitogenic, whereas mixtures including the 9-1 scFvIg were non-stimulatory, confirming the unique properties of the 9-1 IgG3 Fc. Without the IgG3 tail, the bispecific 9.6/9-1 scFvIg was directly mitogenic and was a more potent mitogen than the mAb mixture, but was accessory cell dependent. Unlike the combination of mAb, the bispecific reagent did not directly mobilize calcium in T cells. In comparison to the mAb mixture, bispecific 9.6/9- 1 scFvIg-mediated stimulation of a mixed lymphocyte reaction was significantly more resistant to inhibition of the CD28 co-stimulatory pathway by the inhibitor CTLA-4-Ig. These results show that expression of the 9.6 and 9-1 binding sites together on a bispecific scFvIg increased the mitogenic properties of the mAb and altered the degree of accessory cell signals required for T cell activation.      

维拉帕米增强博莱霉素A5抗癌活性的机制

本文利用流式细胞术(FCM)和动物整体水平的同位素标记药物示踪方法探讨了维拉帕米(VP)增强博莱霉素A₅(BLM)抗癌活性的机制。实验发现VP显著增强BLM对S-180和HEP-2细胞的G₂期阻断效应。VP改变了⁵⁷Co-BLM在荷瘤小鼠部分器官中的分布,增加厂该药在肿瘤中的积聚。VP增強BLM抗癌活性可能是通过增加药物在肿瘤中的积聚,增强药物的G₂期阻断效应以及其它作用实现的。     

Role of zidovudine antiretroviral therapy in the pathogenesis of acquired immunodeficiency syndrome-related lymphoma

The role of zidovudine and other antiretroviral agents in the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related lymphomas has been somewhat controversial. In an attempt to elucidate the precise role of antiretroviral agents in the subsequent development of AIDS-related lymphoma, we performed a population-based, case-control study of human immunodeficiency virus (HIV)-seropositive patients with intermediate- or high-grade lymphoma in Los Angeles County, California, in which information regarding use of antiretroviral medications was ascertained. Diagnostic biopsy material was reviewed to confirm intermediate-or high-grade lymphoma. A structured interview, conducted with all cases and controls, included information about use of zidovudine and other antiretroviral agents. A total of 112 HIV-infected homosexual/bisexual men with lymphoma were matched to 112 homosexual/bisexual men with asymptomatic HIV infection; 49 of the lymphoma cases were also matched to 49 additional controls with AIDS, as defined by conditions other than lymphoma. Positive histories of zidovudine use were reported by 44 (39%) lymphoma cases, 24 (21%) asymptomatic HIV controls, and 21 (42%) AIDS controls. The average duration of zidovudine use up to 12 months before lymphoma diagnosis was 19.0 +/- 13.0 months (mean +/- SD) for the lymphoma cases, 12.6 +/- 10.5 months for the asymptomatic controls, and 11.0 +/- 7.1 months for the AIDS controls. When comparing the 49 HIV-positive lymphoma cases with their 49 matched AIDS controls, all of whom were diagnosed with AIDS during the same time period, the matched relative odds of lymphoma associated with prior use of zidovudine was 0.43 (95% confidence interval [CI] = 0.17 to 1.12). In comparing all 112 lymphoma cases with 49 AIDS controls, the unmatched relative odds of lymphoma associated with zidovudine use was 0.93 (95% confidence interval = 0.47 to 1.83). One lymphoma case and no AIDS control cases had a history of didanosine use; no lymphoma case or AIDS control cases had taken zalcitabine. We conclude that zidovudine is not associated with an increased risk of development of lymphoma among HIV-infected homosexual or bisexual men.