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1.
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
2.
Human neutrophil interactions of a bispecific monoclonal antibody targeting tumor and human Fcγ RIII
L. M. Weiner R. Katherine Alpaugh Anne R. Amoroso Gregory P. Adams David B. Ring Malcolm W. Barth 《Cancer immunology, immunotherapy : CII》1996,42(3):141-150
2B1 is a bispecific murine monoclonal antibody (bsmAb) targeting the c-erbB-2 and CD16 (FcγRIII) antigens. c-erbB-2 is over-expressed
by a variety of adenocarcinomas, and CD16, the low-affinity Fcγ receptor for aggregated immunoglobulins, is expressed by polymorphonuclear
leukocytes (PMN), natural killer (NK) cells and differentiated mononuclear phagocytes. 2B1 potentiates the in vitro lysis
of c-erbB-2 over-expressing tumors by NK cells and macrophages. In this report, the interactions between 2B1 and PMN were
investigated to assess the impact of these associations on in vitro 2B1-promoted tumor cytotoxicity by human NK cells. The
peak binding of 2B1 to PMN was observed at a concentration of 10 μg/ml 2B1. However, 2B1 rapidly dissociated from PMN in vitro
at 37°C in non-equilibrium conditions. This dissociation was not caused by CD16 shedding. When PMN were labeled with 125I-2B1 and incubated at 37°C and the supernatants examined by HPLC analysis, the Fab regions of dissociated 2B1 were not complexed
with shed CD16 extracellular domain. While most of the binding of 2B1 to PMN was solely attributable to Fab-directed binding
to FcγRIII, PMN-associated 2B1 also bound through Fcγ-domain/FcγRII interactions. 2B1 did not promote in vitro PMN cytotoxicity
against c-erbB-2-expressing SK-OV-3 tumor cells. When PMN were coincubated with peripheral blood lymphocytes, SK-OV-3 tumor
and 2B1, the concentration of 2B1 required for maximal tumor lysis was lowered. Although PMN may serve as a significant competitive
binding pool of systemically administered 2B1 in vivo, the therapeutic potential of the targeted cytotoxicity properties of
this bsmAb should not be compromised.
Received: 3 May 1995 / Accepted: 6 February 1996 相似文献
3.
Nathalie Jacobs Alessandra Mazzoni Delia Mezzanzanica Donatella R. M. Negri Olga Valota Maria I. Colnaghi Michel P. Moutschen Jacques Boniver Silvana Canevari 《Cancer immunology, immunotherapy : CII》1997,44(5):257-264
T cell triggering can be achieved by monoclonal antibodies (mAbs) specific for the CD3/TcR complex. In the presence of appropriate
costimulation and/or progression factors, such triggering permits the generation of effector cells for immunotherapy protocols
involving the redirection of T cell lysis against tumor cells by mAbs bispecific for anti-CD3/anti-tumor cells (bs-mAbs).
Focusing our analysis on the clinically relevant bs-mAb OC/TR, we found that bs-mAbs generated with the same anti tumor specificity,
but two other anti-CD3 mAbs, TR66 and OKT3, have the same and a significantly lower lytic potential, respectively, compared
with that of OC/TR. To evaluate the relevance of the anti-CD3 component, we examined several anti-CD3 mAbs with respect to
binding parameters and the ability to trigger T lymphocytes. Competitive binding assays suggested that all anti-CD3 mAbs recognized
the same or overlapping epitopes, although mAbs BMA030 and OC/TR bound with lower avidity than did αCD3 (the bivalent anti-CD3
mAb produced by the hybrid hybridoma OC/TR), TR66 and OKT3, as determined by measurement of the affinity constants. In all
lymphocyte populations examined, which included resting peripheral blood mononuclear cells (PBMC), activated PBMC and T cell
clones, OKT3, BMA033 and OC/TR failed to mobilize Ca2+ without cross-linking, whereas αCD3, in both murine and murine-human chimeric versions, TR66 and BMA030, did not require
cross-linking. The ability to induce CD3 modulation was associated in part with the induction of Ca2+ fluxes. Despite the differences in the behavior of these mAbs in triggering the events that precede proliferation, all of
them ultimately led to expression of the IL-2 receptor and to proliferation in T cells in the presence of accessory cells.
Our data suggest that anti-CD3 mAbs that bind more rapidly (strong Ca2+ mobilizers) and more tightly under physiological conditions are good candidates for retargeting T cells in the bs-mAb clinical
application.
Received: 2 January 1997 / Accepted: 6 February 1997 相似文献
4.
鹅源新城疫病毒ZJ1株微型基因组的构建及其初步应用 总被引:3,自引:0,他引:3
在获得鹅源新城疫病毒ZJ1株全基因组序列的基础上,用增强型绿色荧光蛋白(eGFP)报告基因取代鹅源新城疫病毒ZJ1株整个编码区,只保留与病毒复制、转录和病毒粒子包装相关的调控序列,将其反向克隆入转录载体TVT7R(0.0)中,构建了该毒株的微型基因组。当转染用辅助病毒ZJ1株感染的Hep_2细胞时报告基因得到表达,表明此微型
基因组RNA可被辅助病毒提供的NP、P和L蛋白翻译。同时将该病毒NP、P和L蛋白基因分别克隆入真核表达载体pCI_neo中,构建了表达该病毒NP、P与L蛋白的辅助质粒,用此微型基因组对辅助质粒的表达产物进行了功能鉴定并对该病毒拯救过程中痘苗病毒的最适感染剂量进行了摸索。以上研究为该病毒的成功拯救及开展其它相关研究奠定了基础。 相似文献
5.
Schirrmacher V 《Cancer immunology, immunotherapy : CII》2005,54(6):587-598
For active specific immunotherapy of cancer patients, we designed the autologous virus–modified tumor cell vaccine ATV-NDV. The rationale of this vaccine is to link multiple tumor-associated antigens (TAAs) from individual patient-derived tumor cells with multiple danger signals (DS) derived from virus infection (dsRNA, HN, IFN-). This allows activation of multiple innate immune responses (monocytes, dendritic cells, and NK cells) as well as adaptive immune responses (CD4 and CD8 memory T cells). Preexisting antitumor memory T cells from cancer patients could be activated by antitumor vaccination with ATV-NDV as seen by augmentation of antitumor memory delayed-type hypersensitivity (DTH) responses. In a variety of phase II vaccination studies, an optimal formulation of this vaccine could improve long-term survival beyond what is seen in conventional standard therapies. A new concept is presented which proposes that a certain threshold of antitumor immune memory plays an important role (1) in the control of residual tumor cells which remain after most therapies and (2) for long-term survival of treated cancer patients. This immune memory is T-cell based and most likely maintained by persisting TAAs from residual dormant tumor cells. Such immune memory was prominent in the bone marrow in animal tumor models as well as in cancer patients. Immunization with a tumor vaccine in which individual TAAs are combined with DS from virus infection appears to have a positive effect on antitumor immune memory and on patient survival. 相似文献
6.
本文研究了NDV-CN株对5株不同的人肿瘤细胞的体外杀伤作用。结果表明5株肿瘤细胞对NDV-CN敏感,于感染早期出现细胞收缩变圆,失去贴壁性,感染第5天时细胞存活率低于10%。其中尤以HEP3B细胞最敏感。但NDV-CN株对人二倍体细胞2BS有弱杀伤性。病毒感染早期可检测到感染细胞中有病毒核酸的复制、感染细胞表面有病毒蛋白的表达,脑浆内有病毒粒子存在。NDV-CN株主要诱导HEP3B及T24细胞产生凋亡,主要诱导Hep2、Hela及A549细胞产生坏死。 相似文献
7.
靶向人类免疫缺陷病毒(human immunodeficiency virus,HIV)流行毒株的广谱中和抗体(broadly neutralizing antibody, bNAb)单一疗法最终会导致机体出现病毒逃逸突变,然而基于广谱中和抗体开发的双特异性或多特异性抗体则表现出较好的中和效力和广谱性。根据已公布的单链可变区基因抗体序列,经密码子优化后合成一种由单基因编码的双特异性抗体iMab-PGT151,经双酶切和测序对重组质粒进行了验证。酶联免疫吸附试验检测双特异性抗体的结合特异性,检测U87细胞裂解液中的荧光素酶活性以定量分析双特异性抗体对HIV-1假病毒的中和作用;间接免疫荧光染色法检测双特异性抗体iMab-PGT151对人喉癌上皮细胞的反应性;酶联免疫吸附试验检测该抗体对心磷脂的结合能力,验证其自体反应性。结果显示,构建的双特异抗体iMab-PGT151能够成功表达,可分别结合亲本抗体的各个配体,具有双特异性,能100%中和20株假病毒,IC50值为0.084 μg/mL。与亲本抗体相比,该抗体具有更强的中和效力和广谱度,无自体反应性,具有临床适用性。所构建的双特异性抗体iMab-PGT151将可能成为预防和治疗HIV-1感染的有效候选药物之一。 相似文献
8.
Based on the complete genome sequence of Newcastle disease virus (NDV) ZJI strain, seven pairs of primers were designed to
amplify a cDNA fragment for constructing the plasmid pNDV/ZJI, which contained the full-length cDNA of the NDV ZJI strain.
The pNDV/ZJI, with three helper plasmids, pCIneoNP, pCIneoP and pCIneoL, were then cotransfected into BSR-T7/5 cells expressing
T7 RNA polymerase. After inoculation of the transfected cell culture supernatant into embryonated chicken eggs from specific-pathogen-free
(SPF) flock, an infectious NDV ZJI strain was successfully rescued. Green fluorescent protein (GFP) gene was amplified and
inserted into the NDV full-length cDNA to generate a GFP-tagged recombinant plasmid pNDV/ZJIGFP. After cotransfection of the
resultant plasmid and the three support plasmids into BSR-T7/5 cells, the recombinant NDV, NDV/ZJIGFP, was rescued. Specific
green fluorescence was observed in BSR-T7/5 and chicken embryo fibroblast (CEF) cells 48h post-infection, indicating that
the GFP gene was expressed at a relatively high level. NDV/ZJIGFP was inoculated into 10-day-old SPF chickens by oculonasal
route. Four days post-infection, strong green fluorescence could be detected in the kidneys and tracheae, indicating that
the recombinant GFP-tagged NDV could be a very useful tool for analysis of NDV dissemination and pathogenesis. 相似文献
9.
C. Renner Gerhard Held Sascha Ohnesorge Stefan Bauer Klaus Gerlach Jan-Peter Pfitzenmeier Michael Pfreundschuh 《Cancer immunology, immunotherapy : CII》1997,44(2):70-76
Bispecific monoclonal antibodies (bi-mAb), directed against a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes,
induce activation of resting T lymphocytes and target-specific tumor cell lysis. We now show that both necrosis and apoptosis
contribute to T-cell-mediated tumor cell destruction. Even though T cells up-regulate FAS/APO-1 expression upon bi-mAb stimulation,
FAS/APO-1-mediated apoptosis does not contribute to bi-mAb-mediated destruction of Hodgkin’s cells. CD8+ lymphocytes were the most potent effectors of bi-mAb-mediated cytotoxicity and had the highest levels of mRNA coding for
perforin and granzyme A and B. Ca2+-complexing agents, which abrogate perforin activity, led to decreased levels of necrosis, while inhibition of granzyme activity
in effector or target cells had a similar effect on apoptosis. Granzyme-mediated apoptosis critically dependent on the proliferative
state of the target cells, while perforin-induced necrosis was not cell-cycle-dependent. Our results underline the importance
of the expression levels of perforin and granzymes in the effector T cells and of the proliferative state of the target cells
in bi-mAb-mediated apoptosis and necrosis of tumor cells.
Received: 5 December 1996 / Accepted: 16 January 1997 相似文献
10.
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
11.
Design and characterization of viral polypeptide inhibitors targeting Newcastle disease virus fusion
Paramyxovirus infections can be detected worldwide with some emerging zoonotic viruses and currently there are no specific therapeutic treatments or vaccines available for many of these diseases. Recent studies have demonstrated that peptides derived from the two heptad repeat regions (HR1 and HR2) of paramyxovirus fusion proteins could be used as inhibitors of virus fusion. The mechanism underlying this activity is in accordance with that of class I virus fusion proteins, of which human immunodeficiency virus (HIV) and influenza virus fusion proteins are members. For class I virus fusion proteins, the HR1 fragment binds to HR2 to form a six-helix bundle with three HR1 fragments forming the central coiled bundle surrounded by three coiled HR2 fragments in the post fusion conformational state (fusion core). It is hypothesized that the introduced exogenous HR1 or HR2 can compete against their endogenous counterparts, which results in fusion inhibition. Using Newcastle disease virus (NDV) as a model, we designed several protein inhibitors, denoted HR212 as well asHR121 and 5-Helix, which could bind the HR1 or HR2 region of fusion protein, respectively. All the proteins were expressed and purified using a GST-fusion expression system in Escherichia coli. The HR212 or GST-HR212 protein, which binds the HR1 peptide in vitro, displayed inhibitory activity against NDV-mediated cell fusion, while the HR121 and 5-Helix proteins, which bind the HR2 peptide in vitro, inhibited virus fusion from the avirulent NDV strain when added before the cleavage of the fusion protein. These results showed that the designed HR212, HR121 or 5-Helix protein could serve as specific antiviral agents. These data provide additional insight into the difference between the virulent and avirulent strains of NDV. 相似文献
12.
鸡新城疫病毒HeB02分离株F基因的克隆及其DNA疫苗的研究 总被引:3,自引:0,他引:3
根据GenBank报道的鸡新城疫病毒F基因序列设计了一对引物,以鸡新城疫病毒HeB02分离株基因组为模板,通过RT-PCR扩增出了1·66kb左右的F基因片段,序列分析表明HeB02株F基因与国内标准强毒株F48E9及弱毒疫苗La Sota和Clone30的F基因核苷酸序列的同源性分别为88·1%、84·9%和83·8%。将HeB02株F基因插入真核表达载体pVAX1中,构建了真核表达质粒pSV-F,通过脂质体转染COS-7细胞,SDS-PAGE分析可见表达的特异蛋白条带;Western blot、ELISA和中和试验检测结果表明:真核表达的蛋白与抗新城疫病毒的抗体发生特异性反应,说明F蛋白具有很好的免疫原性。采用活体电击法以真核表达质粒pSV-F免疫3周龄SPF鸡,剂量为50μg/只,3周后加强免疫1次,5周后以100倍鸡胚感染剂量(EID)的F基因同源病毒对所有鸡进行攻毒,攻毒前后每周分别以喉拭子进行病毒分离和HI效价测定。结果显示对照组在攻毒前一直没有检测到抗体效价,攻毒后检测效价为3·0log2±1·40,并且于攻毒后第9天全部死亡;活疫苗组和实验组免疫后第2周检测到抗体效价,第5周最高,HI效价分别为8·3log2±1·30和7·2log2±1·23,攻毒1周后HI效价分别达9·8log2±1·55和8·9log2±1·77,极显著高于对照组(P<0·01)。免疫组未分离到新城疫病毒,对照组全部分离到新城疫病毒。表明所构建的F基因真核表达质粒可作为候选基因疫苗诱导鸡产生免疫保护反应。 相似文献
13.
《MABS-AUSTIN》2013,5(7):1245-1253
ABSTRACTT-cell-dependent bispecific antibodies (TDBs) are promising cancer immunotherapies that recruit patients’ T cells to kill cancer cells. There are many TDBs in clinical trials, demonstrating their widely recognized therapeutic potential. However, their complex, multi-step mechanism of action (MoA), which includes bispecific antigen binding, T-cell activation, and target-cell killing, presents unique challenges for biological characterization and potency assay selection. Here, we describe the development of a single reporter-gene potency assay for a TDB (TDB1) that is MoA reflective and sensitive to binding of both antigens. Our reporter-gene assay measures T-cell activation using Jurkat cells engineered to express luciferase under the control of an NFkB response element. The potencies of select samples were measured both by this assay and by a flow-cytometry-based cell-killing assay using human lymphocytes as effector cells. Correlating the two sets of potency results clearly establishes our reporter-gene assay as MoA reflective. Furthermore, correlating potencies for the same panel of samples against binding data measured by binding assays for each individual arm demonstrates that the reporter-gene potency assay reflects dual-antigen binding and can detect changes in affinity for either arm. This work demonstrates that one reporter-gene assay can be used to measure the potency of TDB1 while capturing key aspects of its MoA, thus serving as a useful case study of selection and justification of reporter-gene potency assays for TDBs. Furthermore, our strategy of correlating reporter-gene potency, target-cell killing, and antigen binding for each individual arm serves as a useful example of a thorough, holistic approach to biological characterization for TDBs that can be applied to other bispecific molecules. 相似文献
14.
Shun-lin HU Qin SUN Qu-zhi WANG Yu-liang LIU Yan-tao WU Xiu-fan LIU 《Virologica Sinica》2007,22(1):34-40
Based on the complete genome sequence of Newcastle disease virus (NDV) ZJI strain, seven pairs of primers were designed to amplify a cDNA fragment for constructing the plasmid pNDV/ZJI, which contained the full-length cDNA of the NDV ZJI strain. The pNDV/ZJI, with three helper plasmids, pCIneoNP, pCIneoP and pCIneoL, were then cotransfected into BSR-T7/5 cells expressing T7 RNA polymerase. After inoculation of the transfected cell culture supernatant into embryonated chicken eggs from specific-pathogen-free (SPF) flock, an infectious NDV ZJI strain was successfully rescued. Green fluorescent protein (GFP) gene was amplified and inserted into the NDV full-length cDNA to generate a GFP-tagged recombinant plasmid pNDV/ZJIGFP. After cotransfection of the resultant plasmid and the three support plasmids into BSR-T7/5 cells, the recombinant NDV, NDV/ZJIGFP, was rescued. Specific green fluorescence was observed in BSR-T7/5 and chicken embryo fibroblast (CEF) cells 48h post-infection, indicating that the GFP gene was expressed at a relatively high level. NDV/ZJIGFP was inoculated into 10-day-old SPF chickens by oculonasal route. Four days post-infection, strong green fluorescence could be detected in the kidneys and tracheae, indicating that the recombinant GFP-tagged NDV could be a very useful tool for analysis of NDV dissemination and pathogenesis. 相似文献
15.
Oliver Manzke Sandra Titzer Hans Tesch Volker Diehl H. Bohlen 《Cancer immunology, immunotherapy : CII》1997,45(3-4):198-202
In advance of using bispecific antibodies for the treatment of B cell lymphoma in humans, we analysed CD3×CD19 bispecific
antibodies for their capacity to induce T cell activiation in cell suspensions from follicular lymphoma lymph nodes. Here,
we demostrate that the lack of costimulatory molecules, such as members of the B7 family, on the tumour cells resulted in
insufficient activation of autologous T lymphocytes. However, stimulation and proliferation of T cells could be induced by
addition of monospecific CD28 antibodies. Moreover, we show that bispecific CD3×CD19 antibodies can protect severe combined
immunodeficiency (SCID) mice from human Epstein-Barr-virus (EBV)-induced B cell lymphoma growth. In these in vivo studies, CD28 costimulation did not show a significant benefit, possibly because of the high-level expression of CD80 and
CD86 on the surface of the lymphoma cells. Furthermore, the treatment of SCID mice with bispecific antibodies, with or without
CD28 antibodies, induced tumour-protective effects, as determined by a rechallenging experiment in long-term-surviving animals
with the autologous EBV-transformed tumour B cell line. Treatment of a follicular lymphoma patient by intratumoural injection
of both antibodies resulted in immunological responses with increases in the T/B ratio of peripheral blood as well as enhanced
NK cell activity without toxic systemic side-effects.
Accepted: 14 October 1997 相似文献
16.
17.
Chezian Somasundaram Robert Arch Siegfried Matzku Margot Zöller 《Cancer immunology, immunotherapy : CII》1996,42(6):343-350
A bispecific F(ab′)2 antibody conjugate (BAC) was constructed against the complement receptor CR3 of macrophages and a variant CD44 (CD44v6) antigen
of rat pancreatic adenocarcinoma cells to redirect macrophage-mediated tumor cytotoxicity. The Fab′ fragments of monoclonal
antibodies (mAb) 1.1ASML and OX42, recognizing the CD44v6 and the CR3 antigens respectively, were chemically coupled at the
hinge region using 5,5′-dithiobis(2-nitrobenzoate). The BAC was characterized in vitro for its specific, dual binding capacity
to CD44v6 and CR3 antigens. Although the monovalence of the BAC resulted in lower avidities to both the antigens as expected,
it was still able to form stable cross-linkages between tumor cells and macrophages in culture leading to the formation of
“clump-like” cell aggregates. The in vitro and in vivo tumor-targeting capacity of the BAC was compared with that of the parental
antitumor mAb 1.1ASML, which mediates tumor killing by antibody-dependent cell cytotoxicity. These results showed that, even
though the bivalent mAb 1.1ASML did not mediate stable cross-linking of target and effector cells, its Fc-receptor-mediated
killing of tumor cells was more effective when compared to the BAC. Thus, this study strongly supports the hypothesis that
firm persistent binding between effector and target cells per se is not as important as the choice of trigger molecule used for macrophage activation to redirect their tumor cytotoxic potential
effectively.
Received: 2 May 1996 / Accepted: 21 May 1996 相似文献
18.
Susan F. Vervoordeldonk Astrid Y. Balkenende H. van den Berg A. E. G. Kr. von dem Borne C. E. van der Schoot E. F. Van Leeuwen Ineke C. M. Slaper-Cortenbach C. E. van der Schoot 《Cancer immunology, immunotherapy : CII》1996,42(1):24-30
Our aim is to treat patients with B cell malignancies with radioimmunotherapy using monoclonal antibodies (mAb) such as CD19,
CD20 and CD22. In this study we investigated the rate of internalization and catabolism of these mAb. After 24 h at 37°C,
20% – 25% of initially cell-bound 125I-CD19 mAb and 125I-CD22 mAb was degraded in B cells, whereas almost no degradation occurred after binding of 125I-CD20 mAb. For B cells expressing Fcγ receptor II (FcγRII), isotype-dependent degradation was noted as the CD19 IgG1 mAb
showed an enhanced degradation rate compared to the switch variant IgG2a. The effect of various pharmaceutical agents that
delay the internalization or subsequent degradation of mAb was evaluated. The degradation was inhibited most effectively by
a combination of etoposide and vinblastine, resulting in accumulation of radioactivity in the target cell. Also the simultaneous
application of CD20 or CD22 with 125I-CD19 mAb or of CD20 with 125I-CD22 mAb proved to be a potent inhibitor of the rapid degradation of these mAb, by inhibiting internalization via an FcγRII-mediated
mechanism. Both methods of reducing the degradation of radioiodinated mAb are expected to prolong irradiation of malignant
B cells and consequently result in an enhanced therapeutic effect in vivo.
Received: 22 September 1995 / Accepted: 13 November 1995 相似文献
19.
Gavin C. Barnard Michelle Zhou Amy Shen Inn H. Yuk Michael W. Laird 《Biotechnology progress》2024,40(1):e3399
Monoclonal antibodies (mAbs) are effective therapeutic agents against many acute infectious diseases including COVID-19, Ebola, RSV, Clostridium difficile, and Anthrax. mAbs can therefore help combat a future pandemic. Unfortunately, mAb development typically takes years, limiting its potential to save lives during a pandemic. Therefore “pandemic mAb” timelines need to be shortened. One acceleration tool is “deferred cloning” and leverages new Chinese hamster ovary (CHO) technology based on targeted gene integration (TI). CHO pools, instead of CHO clones, can be used for Phase I/II clinical material production. A final CHO clone (producing the mAb with a similar product quality profile and preferably with a higher titer) can then be used for Phase III trials and commercial manufacturing. This substitution reduces timelines by ~3 months. We evaluated our novel CHO TI platform to enable deferred cloning. We created four unique CHO pools expressing three unique mAbs (mAb1, mAb2, and mAb3), and a bispecific mAb (BsAb1). We then performed single-cell cloning for mAb1 and mAb2, identifying three high-expressing clones from each pool. CHO pools and clones were inoculated side-by-side in ambr15 bioreactors. CHO pools yielded mAb titers as high as 10.4 g/L (mAb3) and 7.1 g/L (BsAb1). Subcloning yielded CHO clones expressing higher titers relative to the CHO pools while yielding similar product quality profiles. Finally, we showed that CHO TI pools were stable by performing a 3-month cell aging study. In summary, our CHO TI platform can increase the speed to clinic for a future “pandemic mAb.” 相似文献