共查询到20条相似文献,搜索用时 15 毫秒
1.
Yasushi Ohmi Hiroshi Shiku Takashi Nishimura 《Cancer immunology, immunotherapy : CII》1999,48(8):456-462
T helper type1 (Th1) or type2 (Th2) cells were induced from naive Th cells obtained from ovalbumin-specific T cell receptor
(TCR) transgenic mice. Th1 cells producing interferon γ (IFNγ) exhibited stronger antigen-specific cytotoxicity against ovalbumin-(323–339)-peptide-pulsed
A20 tumor cells than did Th2 cells. To develop a general method for applying antigen-nonspecific Th1 cells to tumor immunotherapy,
we examined the targeting of Th1 cells to tumor cells using a bispecific antibody (bsAb) consisting of anti-(mouse CD3) mAb
and anti-(human c-ErbB-2) mAb. When ovalbumin-specific Th1 or Th2 cells were cocultured with c-erbB-2-positive transfectants (CMS7HE), neither type of cell showed significant cytotoxicity or cytokine production in response
to tumor cells. However, addition of bsAb resulted in the triggering of both Th1 and Th2 cells. Th1 cells showed higher levels
of bsAb-dependent cytotoxicity against CMS7HE tumor cells than did Th2 cells. The targeting of Th1 cells to CMS7HE tumor cells
by bsAb also triggered the production of cytokines such as IFNγ, interleukin-2 and tumor necrosis factor α (TNFα). The released
TNFα was demonstrated to be a critical cytolytic factor in bsAb-mediated cytotoxicity by Th1 cells. Finally, Th1 cells were
demonstrated to show antitumor activity in vivo against human c-erbB-2-positive tumor cells implanted in nude mice. These results suggest that Th1 cells are useful effector cells for the application
to adoptive tumor immunotherapy in conjunction with bsAb.
Received: 22 April 1999 / Accepted: 2 July 1999 相似文献
2.
B. J. Kroesen J. Nieken D. T. Sleijfer G. Molema E. G. E. de Vries H. J. M. Groen W. Helfrich T. H. The N. H. Mulder L. de Leij 《Cancer immunology, immunotherapy : CII》1997,45(3-4):203-206
The bispecific monoclonal antibody (bsAb) BIS-1 combines a monoclonal-antibody(mAb)-defined specificity for the CD3 complex,
as present on all T lymphocytes, with a mAb-defined specificity for the pancarcinoma/epithelium associated glycoprotein EGP-2.
In vitro studies indicate that BIS-1 can direct T lymphocytes to kill EGP-2-positive tumour target cells. T cell pre-activation
is necessary for this activity and can be obtained either via incubation of isolated peripheral blood mononuclear cells with
CD3 mAb, followed by short culturing in recombinant interleukin-2-containing medium, or via costimulation with CD5- and CD28-based
bsAb. Clinical application of BIS-1 was started in a pilot study in which carcinoma patients suffering from malignant ascites
or intrapleural effusion were treated. In this study, ex vivo activated autologous lymphocytes were applied locally, i.e.
intraperitoneally or intrapleurally, in the presence of BIS-1. Local inflammation and antitumour activity were observed, whereas
no or only minor systemic toxicity was seen in these patients. Intravenous administration of BIS-1 F(ab′)2 in combination
with subcutaneously given recombinant interleukin-2 (i.v. bsAb/rIL-2 treatment) induced transient but considerable toxicity
including peripheral vasoconstriction, dyspnoea and fever with a maximal tolerated dose of 5–8 μg/kg. High plasma concentrations
of the inflammatory cytokines tumor necrosis factor α and interferon γ were observed at this dose. Whereas bsAb-dictated antitumour
activity could be demonstrated to be present in blood samples of these patients in an in vitro assay, no clear clinical responses
were observed. In a rat model it was found that i.v. bsAb/rIL-2 treatment of EGP-2-positive tumours was effective when a low
systemic tumour burden was present, suggesting that systemic bsAb/rIL-2 treatment might be effective in situations of minimal
residual disease.
Accepted: 14 October 1997 相似文献
3.
Flieger D Kufer P Beier I Sauerbruch T Schmidt-Wolf IG 《Cancer immunology, immunotherapy : CII》2000,49(8):441-448
Cytokine-induced killer cells (CIK), generated in vitro from peripheral blood mononuclear cells (PBMC) by addition of interferon
γ (IFNγ), interleukin-2 (IL-2), IL-1 and a monoclonal antibody (mAb) against CD3, are highly efficient cytotoxic effector
cells with the CD3+CD56+ phenotype. In this study, we evaluated whether the cytotoxicity of these natural-killer-like T lymphocytes against the colorectal
tumor cell line HT29 can be enhanced by the addition of a bispecific single-chain antibody (bsAb) directed against EpCAM/CD3.
For determination of bsAb-redirected cellular cytotoxicity we used a new flow-cytometric assay, which directly counts viable
tumor cells and can assess long-term cytotoxicity. We found that this bsAb induced distinct cytotoxicity at a concentration
above 100 ng/ml with both PBMC and CIK at an effector-to-target cell ratio as low as 1:1. CIK cells revealed higher bsAb-redirected
cytotoxicity than PBMC. Cellular cytotoxicity appeared after 24 h whereas PBMC showed the highest bsAb-redirected cytotoxicity
after 72 h. The addition of the cytokines IL-2 and IFNα but not granulocyte/macrophage-colony-stimulating factor enhanced
bsAb-redirected cytotoxicity of both PBMC and CIK. When the bsAb was combined with the murine mAb BR55-2, which recognizes
the Lewisy antigen, bsAb-redirected cytotoxicity was partly augmented, whereas murine mAb 17-1A, which binds to EpCAM as well, slightly
suppressed bsAb-redirected cytotoxicity induced by the bsAb. We conclude that CIK generated in vitro or in vivo combined with
this new EpCAM/CD3 bsAb and the cytokine IL-2 should be evaluated for the treatment of EpCAM-expressing tumors.
Received: 9 December 1999 / Accepted: 18 May 2000 相似文献
4.
Targeting endothelium for gene therapy via receptors up-regulated during angiogenesis and inflammation 总被引:4,自引:0,他引:4
T. J. Wickham Dorian Haskard David Segal Imre Kovesdi 《Cancer immunology, immunotherapy : CII》1997,45(3-4):149-151
Endothelial cells are an attractive target for gene therapy because they are intimately involved in disease processes associated
with inflammation and angiogenesis and because endothelial cells are readily accessible to gene therapy vectors via the circulation.
Furthermore, specific receptors are up-regulated during angiogenesis or during inflammation. Therefore it should be possible
to target the specific populations of endothelial cells involved in each of these disease processes. We have utilized two
bispecific antibodies to target entry of an adenovirus vector into endothelial cells expressing a receptor up-regulated during
angiogenesis (αv integrins) and a receptor up-regulated during inflammation (E-selectin). Both bispecific antibodies contain the anti-FLAG
M2 mAb, which binds to a FLAG epitope genetically incorporated into the penton base protein of the vector, AdFLAG. The anti-αv-integrin×anti-FLAG bsAb was able to direct binding and entry of AdFLAG into endothelial cells via αv integrins. Likewise, the anti-E-selectin×anti-FLAG bsAb was able to direct binding and entry of AdFLAG into tumor-necrosis-factor(TNF)-activated
endothelial cells via E-selectin. Endothelial cells not activated with TNF were not efficiently transduced by the AdFLAG/E-selectin
bsAb complex. These results demonstrate that bispecific antibodies can be successfully used to target adenovirus to endothelially
expressed receptors that are up-regulated during angiogenesis or inflammation.
Accepted: 14 October 1997 相似文献
5.
Arata Azuma Hideo Yagita Ko Okumura Shoji Kudoh Hisanobu Niitani 《Cancer immunology, immunotherapy : CII》1994,38(5):294-298
Lymphokine-activated killer (LAK) cells exhibit a potent cytotoxicity to malignant cells in vitro. However, a satisfactory effect has not been obtained in many clinical studies except for a few cases. One of the most important reasons why cytolytic activity could not be exhibited in vivo is that LAK cells do not accumulate in the tumor tissue because of a lack of specificity. In the present study, we show the effect of a bispecific antibody (bsAb) on the accumulation of LAK cells around the small-cell lung carcinoma (SCLC) cell and the subsequent enhancement of LAK cell cytotoxicity against SCLC. When short-term (4 days)-cultured LAK cells were used, OKT3xLU246 bsAb, which direct CD3+ T-LAK cells to the target cell, induced a similar level of cytotoxicity to that induced by 3G8xLU246 bsAb, which directs CD16+ LAK cells. Longterm (21 days)-cultured LAK cells exhibited a reduced spontaneous cytotoxicity but retained high cytotoxic activity, which could be directed by OKT3xLU246 or 3G8xLU246 bsAb. The inhibitory effect of LAK cells on tumor cell clonogenicity in soft agar was also enhanced by both bsAb. These results indicate that application of the therapy with LAK cells and OKT3xLU246 bsAb to SCLC patients might be a promising new method of adoptive immunotherapy. 相似文献
6.
Pullarkat V Deo Y Link J Spears L Marty V Curnow R Groshen S Gee C Weber JS 《Cancer immunology, immunotherapy : CII》1999,48(1):9-21
A phase I study of escalating doses of humanized bispecific antibody (bsAb) MDX-H210 with granulocyte-colony-stimulating
factor (G-CSF) was conducted in patients with metastatic breast cancer that overexpressed HER2/neu. The main objectives of
the study were to define the maximal tolerated dose (MTD) of MDX-H210 when combined with G-CSF, to measure the pharmacokinetics
of MDX-H210 when administered with G-CSF, and to determine the toxicity, biological effects and possible therapeutic effect
of MDX-H210 with G-CSF. MDX-H210 is a F(ab)′ × F(ab)′ humanized bispecific murine antibody that binds to both HER2/neu and
the FcγR1 receptor (CD64), and was administered intravenously weekly for three doses followed by a 2-week break and then three
more weekly doses. A total of 23 patients were treated, and doses were escalated from 1 mg/m2 to 40 mg/m2 with no MTD reached. The toxicity of the bsAb + G-CSF combination was modest, with no dose-limiting toxicity noted: 19 patients
had fevers, 7 patients had diarrhea, and 3 patients had allergic reactions that did not limit therapy. The β-elimination half-life
varied from 4 h to 8 h at doses up to 20 mg/m2. Significant release of cytokines interleukin-6, G-CSF, and tumor necrosis factor α was observed after administration of
bsAb. Circulating monocytes disappeared within 1 h of bsAb infusion, which correlated with binding of bsAb, noted by flow-cytometric
analysis. Significant levels of human anti-(bispecific antibody) were measured in the plasma of most patients by the third
infusion. No objective clinical responses were seen in this group of heavily pre-treated patients.
Received: 23 July 1998 / Accepted: 6 November 1998 相似文献
7.
Jamie Honeychurch Andrew Cruise Alison L. Tutt M. J. Glennie 《Cancer immunology, immunotherapy : CII》1997,45(3-4):171-173
Despite the success of mAb and bispecific (bs)Ab in the treatment of certain malignancies, there is still considerable uncertainty
about the most appropriate format in which they should be used. In the current work we have investigated a panel of bsAb [IgG
and F(ab)2] with dual specificity for T cells and neoplastic B cells. Throughout this work, anti-CD2 or anti-CD3 were used to bind the
mouse T cells, and antibodies to surface IgM idiotype (Id), CD19, CD22, or MHC class II were used to target mouse B cell lymphomas
BCL1 or A31. In vitro, killing was measured in a conventional cytotoxicity assay using 51Cr-labelled A31 and BCL1 cells as targets and activated mouse splenocytes as effectors. bsAb showed a wide range of cytotoxic activities, which could
be ranked in the following order: [anti-CD3×anti-class-II]>[anti-CD3×anti-CD19] >[anti-CD3×anti-Id]>[anti-CD3×anti-CD22],
with the [anti-CD2×anti-Id] derivative showing relatively little cytotoxic activity. This hierarchy of activity indicates
some correlation with the binding activity of the bsAb on target cells, but showed a much stronger parallel with the tendency
of the anti-(target cells) mAb to undergo antigenic modulation (less modulation, more killing). In vivo, the situation was
completely different and only the anti-ld derivatives, [anti-CD3×anti-ld] and [anti-CD2×anti-ld], were effective in prolonging
the survival of tumour-bearing animals. Under optimal conditions Id-positive tumour was eradicated with a single treatment
of bsAb. We conclude from this work that the target cell specificity of a bsAb is critical in determining therapeutic outcome
and that in vitro cytotoxicity assays do not predict in vivo activity.
Accepted: 14 October 1997 相似文献
8.
J Brissinck C Demanet M Moser O Leo K Thielemans 《Journal of immunology (Baltimore, Md. : 1950)》1991,147(11):4019-4026
Bispecific antibodies with specificity for the CD3/TCR complex of CTL and a target cell Ag can bridge both cell types and trigger cellular cytoxicity. We have produced bispecific antibodies, directed against the surface-expressed Id of the mouse BCL1 lymphoma and the mouse CD3 complex, by hybrid-hybridoma fusion. Two recombination Ig were purified to homogeneity: B1 X 7D6F, which is univalent for Id and CD3 binding and B1 X 7D6M, which is univalent for Id binding but has lost the CD3 binding because of association of the anti-CD3 H chain with the inappropriate L chain. In vitro studies indicate that bridging the TCR/CD3 complex of resting T cells with tumor IgM Id and the appropriate bispecific antibody induced proliferation and secretion of IL-2. Furthermore, in cytotoxicity assays using 51Cr-labeled tumor cells, preactivated T cells could be targeted with the bispecific antibody to give complete lysis of the Ag+ tumor. Finally, the activity of the bispecific antibody was confirmed in vivo. Animals treated i.v. with 5 micrograms of bispecific antibody 9 days after receiving BCL1 cells were cured. Furthermore, when these animals were checked at 150 days for dormant or variant tumors, as have been reported after other forms of immunotherapy in this model, none could be found. Immunotherapy experiments comparing a mixture of control antibodies with the bispecific antibody demonstrate that tumor cell-T cell bridging is established in vivo and is required for therapeutic success. These results indicate the importance of bispecific antibodies as a novel form of treatment for cancer. 相似文献
9.
Efficient carcinoma cell killing by activated polymorphonuclear neutrophils targeted with an Ep-CAMxCD64 (HEA125x197) bispecific antibody 总被引:3,自引:0,他引:3
Schweizer C Strauss G Lindner M Marmé A Deo YM Moldenhauer G 《Cancer immunology, immunotherapy : CII》2002,51(11-12):621-629
Bispecific antibodies (bsAb) have attracted much attention over the past several years as a mean to improve immunotherapy of cancer. Due to their dual specificity, bsAb are able to redirect effector cells against tumor targets. In this study, the development and preclinical testing of a new quadroma-derived bsAb, HEA125x197, recognizing the tumor-associated Ep-CAM antigen and the high affinity Fc receptor for IgG, CD64, is reported. Using granulocyte-colony stimulating factor (G-CSF) and interferon-gamma (IFN-gamma)-stimulated polymorphonuclear neutrophils to induce CD64 expression, bsAb HEA125 x 197 elicited strong cytotoxic activity towards allogeneic and autologous ovarian carcinoma cells. The cytolytic efficiency of this antibody was comparable to that of a previously described bsAb, HEA125 x OKT3, targeting preactivated T lymphocytes against Ep-CAM-carrying tumor cells. Based on the pan-carcinoma specificity and the stable expression of Ep-CAM, bsAb HEA125x197 may broaden the spectrum of bispecific reagents for the treatment of epithelial malignancies. 相似文献
10.
Immunogenicity increase of autologous tumor cell vaccines by virus infection and attachment of bispecific antibodies 总被引:4,自引:0,他引:4
A new type of cancer vaccine for therapeutic application in cancer patients is described. It consists of three components.
(1) autologous tumor cells, (2) Newcastle Disease Virus (NDV), to be used for infection and (3) bispecific antibodies (bsAb)
which attach to the viral hemagglutinin neuraminidase (HN) molecule on the infected tumor cells. A standardized procedure
has been developed for generating virus infected human autologous tumor cell vaccines (ATV-NDV) which includes cell dissociation,
removal of leukocytes and cell debris, gamma-irradiation and cryopreservation. Infection with the non-virulent strain NDV
Ulster is performed within 30 min of co-incubation. While virus infection already increased immunogenicity of the tumor vaccine,
further augmentation of T cell stimulatory capacity is achieved by attachment of specially designed bi-specific antibodies
(bs HN × CD28 or bs HN × CD3).
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献
11.
Ingmar A. F. M. Heijnen Martin J. Glennie J. G. J. van de Winkel 《Cancer immunology, immunotherapy : CII》1997,45(3-4):166-170
The class I IgG receptor (FcγRI) on cytotoxic effector cells has been reported to initiate destruction of tumour cells by
effector cells in vitro. We are aiming at developing an immunocompetent model to evaluate the cytotoxic capacity of human
FcγRI for the rejection of tumour cells in vivo. Therefore, we recently generated a transgenic mouse strain expressing human
FcγRI on monocytes, macrophages, and neutrophils. In these mice, the human receptor is up-regulated by granulocyte-colony-stimulating
factor (G-CSF) and is able to trigger cellular responses. Subsequently, in the present study the B cell lymphoma IIA1.6 cell
line is selected as a tumour target, and a human FcγRI-directed antitumour bispecific antibody (bsAb) is constructed and characterized.
Fab′ fragments of mAb 22, which bind hFcγRI at an epitope that is distinct from the ligand binding site, were chemically linked
to Fab′ fragments of rat anti-(mMHC class II antigens) mAb M5/114, yielding bsAb 22×M5/114. This bsAb was able to bind simultaneously
to hFcγRI and mMHC class II antigens in a dose-dependent fashion. Binding of 22×M5/114 to FcγRI was not inhibited in the presence
of human IgG. It is important to note that, MHC-class-II-expressing IIA1.6 lymphoma cells were lysed by whole blood from G-CSF-treated
transgenic mice in the presence of bsAb 22×M5/114. No lysis by whole blood from non-transgenic mice or from transgenic animals
that had not received G-CSF was observed. These results indicate that human FcγRI is able to mediate lysis of murine IIA1.6
lymphoma cells by transgenic effector cells via bsAb 22×M5/114. A trial with transgenic mice, evaluating the efficacy of these
hFcγRI-directed bsAb in combination with G-CSF for treatment of IIA1.6 B cell lymphoma, is currently in progress.
Accepted: 14 October 1997 相似文献
12.
Tita-Nwa F Moldenhauer G Herbst M Kleist C Ho AD Kornacker M 《Cancer immunology, immunotherapy : CII》2007,56(12):1911-1920
Due to their dual binding capacity, bispecific antibodies (bsAb) can be used to cross-link cytotoxic effector cells with malignant
targets and may thereby improve adoptive immunotherapy. In this study, the development and preclinical testing of the quadroma-derived
bsAb HD37xT5.16 of the specificity CD19xCD5 is reported. Effector cells used were a population of ex vivo expanded and activated
T cells called cytokine-induced killer (CIK) cells expressing CD5. When combined with CIK cells, the cytolytic potency of
HD37xT5.16 against CD19 positive B cell lymphoma lines was comparable to that observed with a previously described CD19xCD3
bsAb. Further on, we could demonstrate that bsAb CD19xCD5, in contrast to its CD3-binding counterpart, does not induce proliferation
of resting T cells and causes only little activation-induced cell death. Therefore, this novel bsAb binding effector T cells
via CD5 may be particularly useful in combination with adoptive transfer of ex vivo activated T cells, e.g., in the setting
of adoptive immunotherapy after allogeneic stem cell transplantation. The in vitro studies outlined here support the experimental
use of bsAb HD37xT5.16 in preclinical in vivo models for evaluation of its safety and efficacy profile.
Freddy Tita-Nwa and Gerhard Moldenhauer contributed equally to the study and share first authorship. 相似文献
13.
Inez-Anne Haagen Wim B. M. de Lau Bert J. E. G. Bast Anette J. G. Geerars Mike R. Clark Bert C. de Gast 《Cancer immunology, immunotherapy : CII》1994,39(6):391-396
We previously reported that a CD3×CD19 bispecific antibody (bsAb) can induce efficient killing of tumour cells by preactivated T cells isolated from patients with B cell malignancy. For future intravenous application we investigated whether resting T cells from peripheral blood can be stimulated to proliferate and become cytotoxic with the CD3×CD19 bsAb alone. Indeed peripheral blood mononuclear cells, isolated from healthy donors or patients with B cell malignancy, started to proliferate within 1 day in response to CD3×CD19 bsAb. Within the same time spaancytotoxic activity against CD19-positive tumour cells was already detectable. Maintenance of cytotoxic activity was seen during 3 days of culture but optimal lysis of the target cells then required fresh CD3×CD19 bsAb in the cytotoxicity assay. Essentially the same results for proliferation and cytotoxicity were found when separated CD4-positive and CD8-positive T cells were activated by the bsAb in the presence of autologous monocytes. These results may be relevant for the in vivo application of the bsAb when used as immunotherapy in patients with B cell malignancy.This work was supported by grant IKMN 90-10 from the Dutch Cancer Society. M.C. was supported by a grant from the UK Medical Research Couneil 相似文献
14.
T cell activation and retargeting using staphylococcal enterotoxin B and bispecific antibody: An effective in vivo antitumor strategy 总被引:5,自引:0,他引:5
Lewis E. Porter Heidi Nelson I. Ethem Gecim David C. Rice Claude Thibault Andrei I. Chapoval 《Cancer immunology, immunotherapy : CII》1997,45(3-4):180-183
The aim of this work was to test for cure and immunity in a micrometastatic tumor model using in vivo T cell activation with
staphylococcal enterotoxin B (SEB) and retargeting with antitumor×anti-CD3 F(ab′)2 bispecific antibodies (bsAb). All studies were performed in C3H/HeN mice using syngeneic tumor cell lines. For survival studies,
mice were injected intravenously on day 0 with CL62 (a p97-transfected clone of the K1735 murine melanoma tumor). Day-3 treatments
included saline (control), SEB (50 γg intraperitoneal) with or without bsAb (5 μg i.v.). Cured mice, surviving beyond 60 days,
were rechallenged with subcutaneous CL62, K1735, or a nonmelanoma control, AG104. SEB activation studies were performed with
pulmonary tumor-infiltrating lymphocytes isolated from 10-day established CL62 tumors. Maximal tumor-infiltrating lymphocyte
cytotoxicity was demonstrated 24 h following SEB injection, therefore bsAb treatments were administered 24 h after SEB. When
survival was examined at 60 days, there were significantly more survivors in the group receiving SEB plus bsAb (70%) compared
to the group receiving SEB alone (30%), and the controls (0%) (P=0.02 and P<0.01, respectively). Mice cured of CL62 using SEB alone or with bsAb demonstrated equal immunity to CL62, however, mice treated
with SEB plus bsAb were more often immune to the p97– parental cell line, K1735(P=0.001). Ag104 consistently grew in all mice. Results of these studies demonstrate that SEB plus bsAb can be effective, not
only in curing tumors but also in providing protective immunity against targeted and nontargeted tumor antigens.
Accepted: 14 October 1997 相似文献
15.
P. Kufer M. Mack R. Gruber R. Lutterbüse F. Zettl G. Riethmüller 《Cancer immunology, immunotherapy : CII》1997,45(3-4):193-197
Unlike monoclonal antibodies, clinical application of bispecific antibodies has so far lagged behind because of difficult,
low-yield production techniques as well as considerable toxicity attributed to bispecific antibody preparations containing
immunoglobulin-Fc parts and anti-CD3 homodimers [10, 2]. These difficulties were overcome by recombinant generation of a bispecific
single-chain antibody (bscAb) joining two single-chain Fv fragments via a five-amino-acid glycine-serine linker. The anti-CD3
specificity directed against human T cells was combined with another specificity against the epithelial 17-1A antigen. The
following domain arrangement was critical in this individual case to obtain a fully functional bscAb: VL17-1A-VH17-1A-VHCD3-VLCD3. The bscAb was expressed in chinese hamster ovary cells with a yield of 15 mg/l culture supernatant whereas numerous attempts
to obtain a functional protein expression in Escherichia coli failed. The low-molecular-mass bispecific construct (60 kDa) could easily be purified by its C-terminal histidine tail. The
antigen-binding properties are indistinguishable from those of the corresponding univalent single-chain Fv fragments as shown
by enzyme immunoassay and flow cytometry. We could show that the bscAb, which lacks Fc parts and anti-CD3 homodimers is highly
cytotoxic for 17-1A positive tumor cells in nanomolar concentrations and in the presence of human T cells. Most remarkably,
it does not stimulate T lymphocyte proliferation in the absence of tumor cells and, moreover, does not induce CD25 up-regulation
and the secretion of potentially toxic lymphokines such as tumor necrosis factor α, interleukin-6 and interferon γ. Maximal
cytotoxicity (51Cr release) was achieved without notable costimulation and was not further enhanced by adding costimulatory signals such as
those delivered by anti-CD28 antibodies. CD8+ as well as CD4+ T cell subpopulations were recruited to exert cytotoxicity against tumor cells with different kinetics. CD8+ cells induced high 51Cr release within 4 h while CD4+ cells required a 20-h incubation. The systemic application of the 17-1A/CD3-bscAb could be a major improvement in therapy
against disseminated micrometastatic tumor cells. A prospective, randomized clinical trial showing that an anti-17-1A monoclonal
antibody could prolong survival of colorectal cancer patients after 5 and 7 years, warrants an assessment of the clinical
efficacy of this bscAb exhibiting a 1000-fold higher specific cytotoxicity against tumor cells in virto.
Accepted: 14 October 1997 相似文献
16.
《Cytotherapy》2022,24(2):161-171
Background aimsThe authors describe here a novel therapeutic strategy combining a bispecific antibody (bsAb) with cytokine-induced killer (CIK) cells.MethodsThe authors have designed, produced and purified a novel tetravalent IgG1-like CD20 × CD5 bsAb called BL-01. The bsAb is composed of a fused heavy chain and two free light chains that pair correctly to the heavy chain sequences thanks to complementary mutations in the monoclonal antibody 2 CH1/CL sequences.ResultsThe authors show that BL-01 can bind specifically to CD20 and CD5 with an affinity of 4–6 nM, demonstrating correct pairing of two light chains to the fused heavy chain. The CD20 × CD5 BL-01 bsAb has a functional human IgG1 Fc and can induce up to 65% complement-dependent cytotoxicity of a CD20+ lymphoma cell line in the presence of human complement, similar to anti-CD20 rituximab. The bsAb also induces significant natural killer cell activation and antibody-dependent cytotoxicity of up to 25% as well as up to 65% phagocytosis by human macrophages in the presence of CD20+ tumor cells. The BL-01 bsAb binds to CD20 and CD5 simultaneously and can redirect CIK cells in vitro to kill CD20+ targets, increasing the cytotoxicity of CIK cells by about 3-fold. The authors finally show that the CD20 × CD5 BL-01 bsAb synergizes with CIK cells in vivo in controlling tumor growth and prolonging survival of nonobese diabetic/severe combined immunodeficiency mice inoculated with a patient-derived, aggressive diffuse large B-cell lymphoma xenograft.ConclusionsThe authors suggest that the efficacy of bsAb in vivo is due to the combined activation of innate immunity by Fc and redirection of CIK cells to kill the tumor target. 相似文献
17.
Wallace PK Romet-Lemonne JL Chokri M Kasper LH Fanger MW Fadul CE 《Cancer immunology, immunotherapy : CII》2000,49(9):493-503
Objective: The aim was to determine the ability of macrophage-activated killer cells (MAK cells) obtained from peripheral blood of normal
volunteers to kill glioblastoma multiforme (GBM) cell lines. Another goal was to investigate whether a bispecific antibody
(bsAb) MDX-447, recognizing the high-affinity Fc receptor for IgG (FcγRI) and epidermal growth factor receptor (EGFR), would
enhance MAK cell tumoricidal activity. Methods: Monocytes, from leukapheresis product, were isolated by countercurrent elutriation and differentiated into MAK cells by culture
with granulocyte/macrophage-colony-stimulating factor, vitamin D3 and interferon γ. Cells were checked for sterility, endotoxin and phenotypic markers. MAK cell functional activity was measured
by a flow-cytometric phagocytosis assay. Target cells, a carcinoma cell line and two glioma cell lines expressing EGFR, were
stained with PKH-26. MAK cells were labeled with fluorescein-conjugated anti-CD14. Combined effectors, targets and bsAb were
incubated and the percentage of MAK cells with phagocytosed targets was determined by flow cytometry. Conclusion: We demonstrate that a large number of highly purified monocytes, isolated from peripheral blood, can be differentiated into
MAK cells for use as an adjuvant for cancer treatment. After culture these cells are sterile, endotoxin-free and comprise
more than 95% MAK cells. Increased amounts of CD14, CD64 and HLA-DR, which are characteristics of macrophage activation, were
expressed. MAK cells were extremely phagocytic in comparison to monocytes, even in the absence of bsAb. Moreover, bsAb enhanced
the tumoricidal activity of elutriated MAK cells targeted against GBM cell lines. Therefore, intracavity MAK cells armed with
MDX-447 could be an effective adoptive immunotherapy for EGFR-positive GBM.
Received: 5 April 2000 / Accepted: 12 July 2000 相似文献
18.
Natasa Vukovic Samer Halabi Joan Salvador Russo-Cabrera Bart Blokhuis Pedro Berraondo Frank A.M. Redegeld Dietmar M.W. Zaiss 《The Journal of biological chemistry》2022,298(8)
The generation of bispecific antibodies (bsAbs) targeting two different antigens opens a new level of specificity and, compared to mAbs, improved clinical efficacy in cancer therapy. Currently, the different strategies for development of bsAbs primarily focus on IgG isotypes. Nevertheless, in comparison to IgG isotypes, IgE has been shown to offer superior tumor control in preclinical models. Therefore, in order to combine the promising potential of IgE molecules with increased target selectivity of bsAbs, we developed dual tumor-associated antigen-targeting bispecific human IgE antibodies. As proof of principle, we used two different pairing approaches - knobs-into-holes and leucine zipper–mediated pairing. Our data show that both strategies were highly efficient in driving bispecific IgE formation, with no undesired pairings observed. Bispecific IgE antibodies also showed a dose-dependent binding to their target antigens, and cell bridging experiments demonstrated simultaneous binding of two different antigens. As antibodies mediate a major part of their effector functions through interaction with Fc receptors (FcRs) expressed on immune cells, we confirmed FcεR binding by inducing in vitro mast cell degranulation and demonstrating in vitro and in vivo monocyte-mediated cytotoxicity against target antigen-expressing Chinese hamster ovary cells. Moreover, we demonstrated that the IgE bsAb construct was significantly more efficient in mediating antibody-dependent cell toxicity than its IgG1 counterpart. In conclusion, we describe the successful development of first bispecific IgE antibodies with superior antibody-dependent cell toxicity–mediated cell killing in comparison to IgG bispecific antibodies. These findings highlight the relevance of IgE-based bispecific antibodies for clinical application. 相似文献
19.
Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing. 总被引:4,自引:0,他引:4
R Zeidler G Reisbach B Wollenberg S Lang S Chaubal B Schmitt H Lindhofer 《Journal of immunology (Baltimore, Md. : 1950)》1999,163(3):1246-1252
Bispecific Abs (bsAb) are promising immunological tools for the elimination of tumor cells in minimal residual disease situations. In principle, they target an Ag on tumor cells and recruit one class of effector cell. Because immune reactions in vivo are more complex and are mediated by different classes of effector cell, we argue that conventional bsAb might not yield optimal immune responses at the tumor site. We therefore constructed a bsAb that combines the two potent effector subclasses mouse IgG2a and rat IgG2b. This bispecific molecule not only recruits T cells via its one binding arm, but simultaneously activates FcgammaR+ accessory cells via its Fc region. We demonstrate here that the activation of both T lymphocytes and accessory cells leads to production of immunomodulating cytokines like IL-1beta, IL-2, IL-6, IL-12, and DC-CK1. Thus this new class of bsAb elicits excellent antitumor activity in vitro even without the addition of exogenous IL-2, and therefore represents a totally self-supporting system. 相似文献
20.
Ramanathapuram LV Hahn T Graner MW Katsanis E Akporiaye ET 《Cancer immunology, immunotherapy : CII》2006,55(2):166-177
Alpha tocopheryl succinate (α-TOS) is a non-toxic vitamin E analog under study for its anti-cancer properties. In an earlier
study, we showed that α-TOS, when used in combination with non-matured dendritic cells (nmDC) to treat pre-established tumors,
acts as an effective adjuvant. In this study, we have used vesiculated α-TOS (Vα-TOS), a more soluble form of α-TOS that is
relevant for clinical use, in combination with dendritic cells to treat pre-established murine tumors. We demonstrate that
Vα-TOS kills tumor cells in vitro and inhibits the growth of pre-established murine lung carcinoma (3LLD122) as effectively
as α-TOS. The combination of Vα-TOS plus non-matured or TNF-α-matured DC is more effective at inhibiting the growth of established
tumors than Vα-TOS alone. We also observed that Vα-TOS induces expression of heat shock proteins in tumor cells and that co-incubation
of non-matured DC with lysate derived from Vα-TOS-treated tumor cells leads to DC maturation evidenced by up-regulation of
co-stimulatory molecules and secretion of IL-12p70. This study therefore demonstrates the immunomodulatory properties of Vα-TOS
that may account for its adjuvant effect when combined with DC vaccines to treat established tumors.
Supported by Grants 1 RO1 CA94111-02 from the NIH and DAMD 17010126 from the DOD. 相似文献