The cell sensitivity of recombinant human alpha interferons (rIFN-alpha) of greater than 95% purity (A,D and the hybrid A/D) and crude nature (B and F) was studied in human (WISH, HeLa, AG1732), bovine (MDBK, BT), monkey (Vero), mouse (L), rabbit (RK-13), and hamster (BHK-21) cells. Based on an activity of 100% in WISH cells, the other cells responded to rIFN-alpha A as follows: AG1732 (90%), HeLa (94%), and MDBK and BT cells (170-190%). Rabbit, mouse, and hamster cells had a relative sensitivity of less than 1%. rIFN-alpha B and F were essentially equivalent to rIFN-alpha A in terms of cell sensitivity, but MDBK and BT cells were about 20 times more sensitive to rIFN-alpha D than were WISH cells and rIFN-alpha D was 1/5 to 1/10 as active on L cells as on WISH cells. The activity of the hybrid IFN A/D on bovine, mouse, and human cells was similar. The inhibitory dose50 (U/ml) of rIFN-alpha A, B, D, and F against virus infections in WISH cells were: vesicular stomatitis virus (1-4), rhinovirus types 1 and 42 (2-18), and herpes simplex virus (HSV) type 2 (45-70). Type 1 HSV, Semliki Forest (SFV) and encephalomyocarditis (EMC) viruses were tested against only rIFN-alpha A and D where SFV and EMC were the most sensitive to both IFNs (ID50-SFV, 0.2 U/ml, EMC, 1.2 U/ml) while 13 U/ml of rIFN-alpha A and D inhibited Type 1 HSV. The various rIFN-alpha s did not exhibit different antiviral spectra in vitro. When tested in mice rIFN-alpha A did not protect against infections with SFV, EMC, HSV, or influenza viruses. rIFN-alpha D and A/D protected mice infected with EMC, SFV, or HSV.

More than 1600 patients with neoplastic disorders have received recombinant human interferon alfa-2a (Roferon-A, Hoffmann-La Roche, Nutley, NJ) as part of ongoing or completed clinical trials. In this report, the efficacy of interferon alfa-2a therapy was compared with the incidence of antibodies to this interferon in 617 patients who received the drug by intramuscular administration. Antibody measurements were performed using a highly sensitive enzyme immunoassay, and an interferon antiviral neutralization bioassay. Partial or complete remission occurred in 28% (43 of 152) of the antibody-positive patients, and in 24% (112 of 465) of the antibody-negative patients (P = 0.33). The highest incidence of antibody formation occurred among patients with renal cell carcinoma and acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma (44% and 34%, respectively). Both the duration of treatment and length of survival were significantly longer for antibody-positive than for antibody-negative patients. No significant intergroup differences emerged for response rates or for time to onset or duration of therapeutic response. When results from the above assays were compared to those used for the detection of antibodies to recombinant interferon alfa-2b (Intron A, Schering-Plough Inc., Kenilworth, NJ), the immunoradiometric assay method was determined to be seriously deficient for determination of antibody incidence. This decreased assay sensitivity may account for the reportedly lower incidence of antibodies to recombinant alfa-2b interferon.

Peripheral eosinophilia is almost invariably observed during the course of interleukin-2 (IL-2) therapy and is frequently accompanied by the development of a capillary leak syndrome characterized by edema, weight gain, and oliguria. We studied five patients with advanced malignancy treated with IL-2. Eosinophilia was not present initially but developed in all patients late in the course of therapy, with counts ranging from 2,328/mm3 to 15,958/mm3. In all patients, there was a temporal relationship between the infusion of IL-2 and the appearance of elevated plasma concentrations of IL-5, a growth factor for eosinophils. Granulocyte-macrophage colony-stimulating factor was not detectable in plasma. IL-4 and gamma-interferon plasma levels were variably elevated. Plasma concentrations of major basic protein, a toxic eosinophil granule protein, began increasing before eosinophil counts increased. By the time of the third IL-2 infusion, high concentrations of major basic protein were present in all five patients (up to 5,600 ng/mL) and skin biopsies showed major basic protein deposition in the dermis. Four patients developed significant capillary leak syndrome and all of these patients showed markedly elevated major basic protein levels. The lowest peak plasma concentration of major basic protein (1,751 ng/mL) was observed in the one patient who did not develop edema and weight gain. These results suggest that IL-2 induces IL-5 leading to marked peripheral eosinophilia and extravascular eosinophil degranulation. The release of toxic eosinophil products at extravascular sites and in the circulation may contribute to the pathogenesis of the capillary leak syndrome complicating IL-2 therapy.

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L6 and SC IL-2 were well tolerated in the majority of patients when given in the outpatient setting. In view of the clinical efficacy of this combination, more phase II trials are warranted.

Peripheral eosinophilia is almost invariably observed during the course of interleukin-2 (IL-2) therapy and is frequently accompanied by the development of a capillary leak syndrome characterized by edema, weight gain, and oliguria. We studied five patients with advanced malignancy treated with IL-2. Eosinophilia was not present initially but developed in all patients late in the course of therapy, with counts ranging from 2,328/mm3 to 15,958/mm3. In all patients, there was a temporal relationship between the infusion of IL-2 and the appearance of elevated plasma concentrations of IL-5, a growth factor for eosinophils. Granulocyte-macrophage colony-stimulating factor was not detectable in plasma. IL-4 and gamma-interferon plasma levels were variably elevated. Plasma concentrations of major basic protein, a toxic eosinophil granule protein, began increasing before eosinophil counts increased. By the time of the third IL-2 infusion, high concentrations of major basic protein were present in all five patients (up to 5,600 ng/mL) and skin biopsies showed major basic protein deposition in the dermis. Four patients developed significant capillary leak syndrome and all of these patients showed markedly elevated major basic protein levels. The lowest peak plasma concentration of major basic protein (1,751 ng/mL) was observed in the one patient who did not develop edema and weight gain. These results suggest that IL-2 induces IL-5 leading to marked peripheral eosinophilia and extravascular eosinophil degranulation. The release of toxic eosinophil products at extravascular sites and in the circulation may contribute to the pathogenesis of the capillary leak syndrome complicating IL-2 therapy.