ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

Despite much recent progress, human monoclonal antibodies (HuMAbs) are currently more difficult to generate than conventional rodent monoclonals. Clinical trials using rodent monoclonals suggest that they can be given safely, but that the human antimouse immune response can limit their efficacy. We review the human monoclonals that have been generated to date, and explore the clinical uses that will be made of these reagents in the near future.

ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

We report results of 24-h continuous infusions of murine monoclonal antibody T101 in six patients with chronic lymphocytic leukemia (CLL), and 10 with cutaneous T-cell lymphoma (CTCL), at doses of 10, 50, 100, or 500 mg. Similar side-effects were seen in CLL and CTCL, including direct toxic effects of therapy, such as fever, sweats, and chilling, and a 30% frequency of allergic manifestations. In vivo binding of T101 to target cells in blood, skin, lymph nodes, tumor masses, and bone marrow was demonstrated. Antigenic modulation occurred rapidly in all cases, and persisted throughout the infusion period. Peak serum T101 levels for equivalent doses were somewhat higher, and persisted longer in CTCL, perhaps because of differences in the number of circulating target cells. Antimouse antibodies were demonstrated in 5 of 10 CTCL vs. 0 of 6 CLL patients. In all five cases, there was a substantial component of T101 specificity in the antimouse response. Brief objective clinical responses were observed in 4 of 10 CTCL and 2 of 6 CLL patients. Acute antitumor effects of T101 were substantially more dramatic in CTCL than CLL, but appeared limited by antigenic modulation and the emergence of antimouse antibodies. In view of the in vivo binding and modulation, more durable antitumor effects may be achievable with cytotoxic immunoconjugates of this monoclonal antibody.

ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

Recombinant human interleukin-2 (rIL-2, courtesy of Cetus Corporation, Emeryville, CA, U.S.A.) is highly effective in eradicating syngeneic tumor when administered to C57BL/6 mice implanted with a nonimmunogenic, rapidly growing clone of B16 melanoma, or an immunogenic methylcho-lanthrene-induced sarcoma, 1–3 days, before beginning treatment at 5 χ 104U/injection daily for 5 days, and then on alternate days for 4 weeks. Low-dose cyclophosphamide (CY, 50 mg/kg), injected intraperitoneally (i.p.) 4 times at weekly intervals, greatly facilitated tumor eradication in rIL-2-treated mice. Most early subcutaneous (s.c.) tumors were cured by combining CY i.p. with repeated perilesional s.c. injections of rIL-2, i.e, 100% cure for 1-day and 87–91% for 3-day melanomas. When rIL-2 was administered without CY, the cure rate was 64% for 1-day and 67% for 3-day melanomas. This cure rate indicated a synergism between rIL-2 and CY, since CY alone did not affect tumor incidence. CY was therefore administered in all subsequent experiments. Treatment with rIL-2, localized to the site of the melanoma or sarcoma, was most effective, although systemic (i.p.) administration achieved results regardless of tumor site. When either tumor was implanted s.c. and rIL-2 treatment was also given s.c. locally, beginning 1–3 days later, 87–100% of the mice were cured, compared with 35–50% cured when rIL-2 was administered i.p., and 0% cured in excipient buffer-injected controls. Conversely, with i.p. treatment of i.p. tumors, 60–83% of the mice were tumor-free on day 50, as compared with only 17% tumor-free if treatment was s.c. These in vivo model systems should prove useful in helping establish protocols for human therapy.

ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

In vitro synergism between interferons (IFNs) and chemothera-peutic drugs has been demonstrated, and an enhancement of IFN's antiprolif-erative effects when combined with cimetidine has been suggested in melanoma patients. In this pilot study, 12 patients with advanced malignant melanoma received HuIFNp by 30 min i.v. infusion at 30 χ 106u/m2day for 4 days, followed by i.v. decarbazine (DTIC) 1.0 g/m2on day 5, repeated every 4 weeks. Oral cimetidine, 300 mg q.i.d., was given continuously. All the patients had visceral (bulky) metastases. No objective responses were observed; however, two patients had stable diseases for 16 and 20 weeks, respectively. Mild chills and fever with IFN, and mild to moderate emesis with DTIC, were noted. No additive haemopoietic or hepatic toxicity was observed. Combination of HuIFNβ, DTIC, and cimetidine is relatively nontoxic, but does not appear to have a significant antitumour activity in patients with advanced malignant melanoma.

ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

Forty-two male homosexuals and/or hemophiliacs with depressed helper/suppressor T-cell ratios were treated with one of three different doses of thymosin fraction 5 (TF5, 30, 60, and 120 mg), or a single dose of thymosin Alpha One (TA1, 600 μ.g), by daily subcutaneous (SQ) administration for 10 weeks, followed twice weekly for 4 weeks. No major toxicity was noted for any of the preparations tested, although three subjects treated with TF5 had to discontinue therapy because of severe local skin reactions. Of the doses and preparations tested, only 60 mg TF5 was capable of significantly improving (p < 0.02) mean T-cell lymphoproliferative responses to alloantigens (MLR) for six HTLV-III seropositive subjects who were abnormal prior to therapy. Peripheral blood lymphocytes from subjects treated with 60 mg TF5 also exhibited a transient restoration of mean mitogen-induced interleukin-2 (IL-2) production to normal. No effects were observed with any of the four treatment regimens on absolute helper T-cell numbers, NK activity, antibody tilers to HTLV-III, or in the expression of a variety of surrogate markers for acquired immunodeficiency syndrome (AIDS). Four of the six seropositive subjects treated with 60 mg TF5 exhibited a return to depressed baseline MLR, after switching to twice weekly injections. With a median follow-up time of 20 months, six cases of AIDS developed. However, none of the five subjects whose MLR improved following treatment progressed to AIDS. We recommend daily subcutaneous (SQ) administration of 60 mg (40 mg/m2) TF5 for use in combined modality trials, along with drugs capable of suppressing replication of HTLV-III.

ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

A new class of synthetic biological response modifiers (BRMs) has been produced by combining a highly electrophilic reactant, 2-methyl-2, 5-di-hydrofuran (a cyclic acetal of cis-3-acetyl acrolein), with L-ascorbic acid. The parent class of compounds can be referred to as methylfurylbutyrolactones (MFBL), previously termed Nafocare B. This parent molecule is amorphous, has a molecular weight of 252.7, and the chemical name [3,6] cyclohemiketal of 2-(5-methyl-2-furyl)-3-keto-L-butyrolactone. Two crystalline forms were produced by a reaction of the MFBL parent molecule with either succinic anhydride or succinimide, to create MFBL-SA (Nafocare B2) and MFBL-S (Nafocare B3) dimers, respectively. The structure of these compounds has been confirmed by modern methods of analytical chemistry, including x-ray crystallography. All three forms of the MFBLs showed negligible toxicity in single-dose acute LD-50s in mice. Also, the MFBLs did not demonstrate genotoxic activity at 800 mg/kg in the mouse micronucleus assay. The MFBLs are immunostimulatory in assays involving T- and B-lymphocytes, but not in im-munoassays on macrophages derived from resident- or thioglycollate-elicited peritoneal exudate cells (PEC). Spleen cells from mice treated 4 days via the intraperitoneal, intravenous, or the oral routes responded significantly over controls to suboptimal stimulatory concentrations of polyclonal mitogens in the lymphocyte stimulation assay. The MFBLs were not mitogenic, since they did not increase DNA synthesis in resting spleen cells from MFBL-treated mice. Antibody production is also amplified by the MFBLs. Mice immunized with sheep erythrocytes, a T-cell-dependent antigen, and treated with MFBLs had a 200–800% increase in the numbers of antibody-producing splenic lymphocytes detected by the Jerne hemolytic plaque assay. Also, mice immunized with soluble bovine serum albumin (BSA), and treated with a MFBL, demonstrated at least a fourfold increase in IgG-specific antibodies to BSA, when compared with controls. To demonstrate effects of MFBLs on.

ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

The effect on the respiratory burst of murine splenic cells after in vitro exposure to nontoxic monophosphoryl lipid A (MPL), toxic diphosphoryl lipid A (DPL), and refined standard endotoxin (RSE) was studied by luminol-dependent, zymosan-stimulated chemiluminescence (CL). CL was stimulated only to a minimum degree by 0.1 μg of MPL, DPL, or RSE, but this was clearly increased when 10-fold higher doses were used. CL activity generated by RSE, which contains only lipid A and ketodeoxyoctanate, remained at a moderate level, even when 100-fold higher doses were used. In contrast, keto-deoxyoctanate-free DPL elevated CL in a dose-dependent manner. Nontoxic MPL at a high dose significantly enhanced CL generation to levels that were comparable to those stimulated by DPL. In addition, phagocytosis of freshly prepared fluorescent beads by adherent peritoneal macrophages was enhanced seven- to 10-fold by toxic DPL and reference LPS, and fivefold by nontoxic MPL.

ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

ICR mice infected withSchistosoma mansonideveloped sizable concomitant immunity to a challenge infection 10 weeks, but not 7 weeks, following the primary infection. At 7 weeks, postprimary-infection mice exhibited increased resistance to reinfection when treated with BCG or MDP. BCG even rendered noninfected mice resistant to infection. Macrophage function inhibitors such as silica and trypan blue did not abolish the concomitant immunity state, but they increased the worm burden due to a single infection, whether given before or after the infection. The onset of concomitant immunity in infected mice was paralleled by the appearance in their peritoneal exu-date of schistosomulicidal-adherent macrophages. Such cells were evident at 9 but not 7 weeks of infection. The in vivo injection of MDP accelerated their appearance in infected mice, while silica, trypan blue, and carrageenan abolished it. The findings suggest that highly activated schistosomulicidal macrophages develop in infected mice, and might participate in the destruction of the invading parasite.

ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID

摘要:

Interferon (IFN) treatment has been shown to suppress the bone marrow in mice and humans, causing a leukopenia. In vitro studies with the mouse system have shown that colony stimulating factors (CSFs) antagonize the bone marrow suppressive, but not the antiviral or antiproliferative activities of IFNs. Partially purified murine macrophage colony stimulating factor (CSF-1) was evaluated for its ability to antagonize the myelosuppressive effect of murine (Mu) IFNs in vivo. All three interferon types (MuIFN-α, MuIFN-β, and MuIFN-α) were used. IFNs and CSF-1 were administered subcutaneously for 3 successive days, blood was drawn by retro-ocular bleeding, and myelo-suppression was quantitated by subjecting the blood to total white blood cell (WBC) counts and to differential counts. The IFNs had similar effects, though MuIFN-α was a significantly more potent (50− to 100-fold) myelosuppressive agent than MuIFN-α or MuIFN-β. Treatment with each of the three IFNs caused a reduction in the total WBC count (up to 40% reduction) and a generalized reduction of each of the three major leukocytes (lymphocytes, segmented polymorphonuclear leukocytes, and monocytes). Treatment with CSF-1 did not affect the total WBC count, but did cause a shift in the relative ratios of the leukocytes, decreasing the relative percentage of lymphocytes, and increasing the relative percentage of segmented polymorphonuclear leukocytes and monocytes. Combined treatment with CSF-1 and IFN inhibited the myelosuppressive activity of the IFNs, and restored the total WBC count to control levels. This restoration was largely due to increased levels of segmented polymorphonuclear leukocytes and monocytes. The data support the concept that the simultaneous administration of CSFs may be of use in moderating the myelosuppressive effects of IFNs during IFN therapy for viral diseases and cancer.

ISSN:0732-6580    

出版商:OVID    

年代:1986

数据来源: OVID