English articles on abatacept, golimumab, and tocilizumab in rheumatoid arthritis published between 2002 and 2009 were reviewed systematically. All randomized clinical trials, open-label extensions, meta-analyses, and reviews were examined. There were thirteen articles on abatacept, four on golimumab, and seven on tocilizumab. All three drugs were effective in methotrexate-naive, methotrexate-incomplete responders, and tumor-necrosis-factor-failure rheumatoid arthritis patients. Of the three, only abatacept has been tested in a head-to-head trial with infliximab, in which it was found to be equivalent to infliximab. Golimumab resulted in a more modest improvement than the others in methotrexate-naive patients, although no direct comparisons among the three drugs were possible or appropriate. Descriptive analysis of adverse events showed that patients receiving abatacept, golimumab, and tocilizumab were subject to more adverse events than controls overall, as expected. In the abatacept studies, a few cases of tuberculosis, more cardiovascular events and gastrointestinal bleedings and more basal cell carcinoma were seen. Golimumab was associated with more skin rashes and pneumonia, while tocilizumab was associated with increased lipids, more liver-function abnormalities, and neutropenia. These new medications are useful additions to the rheumatologic armamentarium and represent greater convenience (golimumab) or different mechanisms of action (abatacept and tocilizumab) than tumor-necrosis-factor inhibitors for treating rheumatoid arthritis. As expected, some adverse events occur when using these drugs and patients need to be watched carefully.
Antibodies, Monoclonal/*administration & dosage/adverse effects ; Antirheumatic Agents/*administration & dosage/adverse effects ; Arthritis, Rheumatoid/*drug therapy ; Biological Therapy ; Humans ; Immunoconjugates/*administration & dosage/adverse effects

To facilitate the establishment of mixed chimerism with limited dose of bone marrow (BM) cells, and to achieve tolerance in skin graft model, combined blocking of costimulatory pathway and IL-2 pathway was used in minimally myeloablative model using busulfan. BM cells (2.5 x 10(7)) of BALB/c were injected into C57BL/6 mice at day 0 with full thickness skin graft after single dose injection of busulfan (25 mg/kg) on day-1. Recipients were grouped and injected the anti-CD154, CTLA4-Ig, anti-IL-2R at days 0, 2, 4, and 6 according to protocol. Mixed macrochimerism were induced in groups treated with anti-CD154+anti-CTLA4-Ig, anti-CD154+anti-IL-2R, and anti-CD154+anti-CTLA4 Ig+anti-IL-2R. Three groups having chimerism enjoyed prolonged graft survival more than 6 months. Superantigen deletion study revealed deletion of alloreactive T cells in combined blockade treated groups. In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154. However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation. In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft.
Skin Transplantation/*immunology/methods ; Mice, Inbred BALB C ; Mice ; Male ; Interleukin-2/*immunology ; Immunoconjugates/*administration & dosage ; Graft Survival/*immunology ; Drug Combinations ; CD40 Ligand/*immunology ; Bone Marrow Transplantation/*immunology/methods ; Antibodies/*administration & dosage/immunology ; Animals

To facilitate the establishment of mixed chimerism with limited dose of bone marrow (BM) cells, and to achieve tolerance in skin graft model, combined blocking of costimulatory pathway and IL-2 pathway was used in minimally myeloablative model using busulfan. BM cells (2.5 x 10(7)) of BALB/c were injected into C57BL/6 mice at day 0 with full thickness skin graft after single dose injection of busulfan (25 mg/kg) on day-1. Recipients were grouped and injected the anti-CD154, CTLA4-Ig, anti-IL-2R at days 0, 2, 4, and 6 according to protocol. Mixed macrochimerism were induced in groups treated with anti-CD154+anti-CTLA4-Ig, anti-CD154+anti-IL-2R, and anti-CD154+anti-CTLA4 Ig+anti-IL-2R. Three groups having chimerism enjoyed prolonged graft survival more than 6 months. Superantigen deletion study revealed deletion of alloreactive T cells in combined blockade treated groups. In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154. However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation. In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft.
Skin Transplantation/*immunology/methods ; Mice, Inbred BALB C ; Mice ; Male ; Interleukin-2/*immunology ; Immunoconjugates/*administration & dosage ; Graft Survival/*immunology ; Drug Combinations ; CD40 Ligand/*immunology ; Bone Marrow Transplantation/*immunology/methods ; Antibodies/*administration & dosage/immunology ; Animals

OBJECTIVETo evaluate the growth inhibitory effect of adriamycin (ADM) conjugated to an anti-lung cancer single-chain antibody (ScFv) 2A7-1 on lung adenocarcinoma cell line A2 in vitro.

METHODS2A7-1 cell culture medium was concentrated by ultra-filtration (with Amicon P10Z filter), and soluble ScFv was purified using RPAS purification kit. ADM was conjugated to 2A7-1 by glutaraldehyde. A(280) and A(490) of the conjugate 2A7-1-ADM were determined by spectrophotometry and the molar ratio of 2A7-1 to ADM was calculated. Immunoreactivity of the conjugate was detected by immunohistochemistry. Its growth inhibitory effect on lung adenocarcinoma cell line A2 was determined by colony formation assay in vitro.

RESULTSThe molar ratio of 2A7-1 to ADM was 1:3.2. The conjugate strongly reacted with A2 cell. Its growth inhibitory effect on A2 cells was 4 times as potent as ADM.

CONCLUSIONAdriamycin conjugated to anti-lung cancer single-chain antibody 2A7-1 has much higher cytotoxic activity than unconjugated adriamycin against human lung adenocarcinoma.

Adenocarcinoma ; immunology ; pathology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Colony-Forming Units Assay ; Doxorubicin ; administration & dosage ; pharmacology ; Humans ; Immunoconjugates ; pharmacology ; Immunoglobulin Variable Region ; chemistry ; pharmacology ; Lung Neoplasms ; immunology ; pathology

OBJECTIVETo investigate the influence of low doses of granulocyte macrophage colony stimulating factor on the allogeneic antigen (Ag) ingestion capacity of immature dendritic cells (GM low DC), and subsequently the changes in the cellular phenotype and function.

METHODSMononuclear cells from C57BL/6 mice was labelled with 3H-Leu to make Ag supernatant. The Ag supernatant was cocultured with GM low DC or mature DC for 30,60 and 90 mins, then cpm value were determined. The changes in I(A)/I(E) and CD80 on cell surface after antigen ingestion were determined with flow cytometry (FCM). By using mixed lymphocyte reaction (MLR), the cells were divided into control (non-sensitized T lymphocyte), GM low DC, GM low DC and allogeneic antigen, GM low DC and allogeneic antigen and CTLA-4 Ig groups. The cpm value in each group was recorded and the stimulation index (SI) was calculated.

RESULTSUpon 30, 60 and 90 mins of allogeneic Ag stimulation, the cpm value of GM low DC was obviously higher than that of mature DC (P < 0.05 or 0.01). In addition, the expression of I(A)/I(E) and CD80 before allogeneic Ag ingestion were significantly higher than those after Ag ingestion (I(A)/I(E): 32 +/- 8% vs. 54 +/- 10, P < 0.05; CD80: 25 +/- 10% vs. 71 +/- 18%, P < 0.01). MLR: Compared with control group, the cpm value in GM low DC with allogeneic Ag group was increased markedly (P < 0.05), with SI higher than 2.0, while no difference was found among control, GM low DC group, GM low DC and allogeneic Ag and CTLA-4Ig groups (P > 0.05), with SI lower than 2.0

CONCLUSIONThough GM low DC exhibits powerful antigen ingestion capacity, the cell phenotype and function will get mature gradually. Immune tolerance can be established by incubating GM low DC with CTLA-4Ig.

Abatacept ; Animals ; Antigens ; immunology ; Dendritic Cells ; cytology ; immunology ; Female ; Granulocyte-Macrophage Colony-Stimulating Factor ; administration & dosage ; pharmacology ; Immune Tolerance ; drug effects ; Immunoconjugates ; pharmacology ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL

Recently the use of peptides in bee venom (PBV) for cancer therapy has attracted considerable attention. In this study, the sterically stabilized liposomal PBV (PBV-SL) was prepared using soybean phosphatidylcholine, cholesterol, and cholesterol-PEG-COOH. The humanized antihepatoma disulfide-stabilized Fv (hdscFv25) was coupled to sterically stabilized liposomes using the N-hydroxysuccinimide ester method. The hdscFv25-immunoliposomes (SIL[hdscFv25]) were immunoreactive as determined by ELISA assay. SIL[hdscFv25] showed higher tumor cells selectivity. PBV-SIL[hdscFv25] can kill SMMC-7721 cells in vitro with higher efficiency than non-targeted liposomes. Whereas cytotoxicties were compared for Hela cells, no significant differences was observed between PBV-SIL[hdscFv25] and PBV-SL. Sterically stabilized immunoliposomal peptides in bee venom could be one drug targeting delivery system.
Antineoplastic Agents ; administration & dosage ; pharmacology ; Bee Venoms ; chemistry ; Carcinoma, Hepatocellular ; pathology ; Cell Line, Tumor ; Cell Survival ; drug effects ; Cholesterol ; chemistry ; Drug Delivery Systems ; HeLa Cells ; Humans ; Immunoconjugates ; chemistry ; pharmacology ; Liposomes ; chemistry ; Liver Neoplasms ; pathology ; Melitten ; administration & dosage ; isolation & purification ; pharmacology ; Peptides ; administration & dosage ; isolation & purification ; pharmacology ; Recombinant Proteins ; administration & dosage ; pharmacology

OBJECTIVETo investigate the effect of antibody-targeted chemotherapy against human prostate cancer LNCaP cells in vitro.

METHODSThe monoclonal antibody 7E11C5.3 against human prostate cancer was conjugated to pingyangmycin (PYM), mediated by dextran T-40, and the immunoreactivity of 7E11C5.3 was determined by indirect enzyme-linked immunosorbent assay. The bacteriostatic activity of the conjugate was determined using TTC assay, and its cytotoxicity against LNCaP cells was determined by MTT assay.

RESULTSThe 7E11C5.3:PYM molar ratio was l:54 in the conjugate, and the immunoreactivity of 7E11C5.3 was decreased by approximately 10% to 20% after conjugation. The bacteriostatic activity of conjugated PYM was 25% of that of free PYM. The 50% inhibitory doses (IC50) of 7E11C5.3-PYM conjugate and free PYM against the in vitro cultured LNCaP cells were 9.41-/+1.98 microg/ml and 29.92-/+7.88 microg/ml, respectively.

CONCLUSION7E11C5.3-PYM conjugate displays stronger cytotoxicity against anti-prostate cancer effects than free PYM.

Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; Antibodies, Monoclonal ; administration & dosage ; pharmacology ; Bleomycin ; administration & dosage ; analogs & derivatives ; pharmacology ; Cell Line, Tumor ; Cell Survival ; drug effects ; Cytotoxicity, Immunologic ; drug effects ; immunology ; Drug Delivery Systems ; Humans ; Immunoconjugates ; administration & dosage ; pharmacology ; Male ; Prostatic Neoplasms ; immunology ; pathology

AIMTo study the antitumor effects of an immunoconjugate composed of lidamycin (LDM) and monoclonal antibody 3G11 (3G11-LDM conjugate).

METHODS3G11-LDM conjugate was prepared by using 2-iminothiolane (2-IT) and m-maleimidobenzoyl-N-hydroxy-succimide ester (MBS) as crosslinkers. The molecular weight of the conjugate was measured on non-reduced SDS-PAGE gel. Immunoreactivity of 3G11-LDM conjugate to type IV collagenase or to hepatoma 22 cells was determined by ELISA. The cytotoxicity of the immunoconjugate to hepatoma 22 cells was examined by MTT assay. Antitumor effects of the 3G11-LDM conjugate in vivo were evaluated using subcutaneously transplanted hepatoma 22 tumor model in mice.

RESULTSThe molecular weight of 3G11-LDM conjugate was approximately 160 kDa. 3G11-LDM conjugate retained part of the immunoreactivity of 3G11 to type IV collagenase and hepatoma 22 cells. As compared with free LDM, 3G11-LDM conjugate showed stronger cytotoxicity to hepatoma 22 cells. When administered intravenously (i.v. x 2 on day 1 and 8), 3G11-LDM conjugate, at doses of 0.05 and 0.10 mg.kg-1, inhibited the growth of hepatoma 22 in mice by 87.8% and 97.2% on day 11, respectively, whereas the unconjugated LDM at 0.05 mg.kg-1 inhibited tumor growth by 67.1%. The median survival times for tumor-bearing mice of untreated control, LDM at 0.05 mg.kg-1, 3G11-LDM at 0.05 mg.kg-1, and 3G11-LDM at 0.10 mg.kg-1 were 34, 41.5, 60.5 and 94 d, respectively. Evidently 3G11-LDM was more effective than free LDM in suppressing tumor growth and prolonging the life span of tumor-bearing mice.

CONCLUSION3G11-LDM conjugate shows much stronger antitumor effects than equivalent dose of free LDM and may have promising therapeutic potential in cancer treatment.

Aminoglycosides ; administration & dosage ; therapeutic use ; Animals ; Antibiotics, Antineoplastic ; administration & dosage ; therapeutic use ; Antibodies, Monoclonal ; immunology ; Cell Division ; drug effects ; Disease Models, Animal ; Enediynes ; Female ; Immunoconjugates ; therapeutic use ; Liver Neoplasms, Experimental ; drug therapy ; pathology ; Matrix Metalloproteinase 2 ; immunology ; Matrix Metalloproteinase 9 ; immunology ; Mice ; Neoplasm Transplantation ; Random Allocation ; Tumor Cells, Cultured