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1.
Siegfried Matzku Harald Krempel Hans-Peter Weckenmann Volker Schirrmacher Hannsjörg Sinn Herbert Stricker 《Cancer immunology, immunotherapy : CII》1990,31(5):285-291
Summary The potential of small unilamellar liposomes coupled to anti-tumour monoclonal antibodies (immunoliposomes) to accumulate in solid tumour tissue was tested in two systems, i.e. a human malignant melanoma xenografted into nude mice and a syngeneic murine lymphoma ESb.Mp exhibiting spontaneous metastasis to the liver. Both monoclonal antibodies tested were partly released from immunoliposomes within a few hours, thus generating a seemingly constant level of circulating antibody. Nevertheless it was possible to follow the biodistribution of intact immunoliposomes by virtue of a radioiodine label incorporated into the lipid moiety. It was found that in both tumor systems, though they differed with respect to the size of lesions and maybe also to the vascular architecture of surrounding tissue, immunoliposome uptake was virtually nil. The blockade of uptake into solid tumour tissue was caused by the limited availability of immunoliposomes due to their moderate stability, but especially by the inability of the particulate carrier to extravasate. 相似文献
2.
Advantage of residualizing radiolabels for an internalizing antibody against the B-cell lymphoma antigen, CD22 总被引:1,自引:0,他引:1
Robert M. Sharkey Thomas M. Behr M. Jules Mattes Rhona Stein Gary L. Griffiths Lisa B. Shih Hans J. Hansen Rosalyn D. Blumenthal Robert M. Dunn Malik E. Juweid D. M. Goldenberg 《Cancer immunology, immunotherapy : CII》1997,44(3):179-188
LL2 is an anti-CD22 pan-B-cell monoclonal antibody which, when radiolabeled, has a high sensitivity for detecting B-cell,
non-Hodgkin’s lymphoma (NHL), as well as an antitumor efficacy in therapeutic applications. The aim of this study was to determine
whether intracellularly retained radiolabels have an advantage in the diagnosis and therapy of lymphoma with LL2. In vitro
studies showed that iodinated LL2 is intracellularly catabolized, with a rapid release of the radioiodine from the cell. In
contrast, residualizing radiolabels, such as radioactive metals, are retained intracellularly for substantially longer. In
vivo studies were performed using LL2-labeled with radioiodine by a non-residualizing (chloramine-T) or a residualizing method
(dilactitol-tyramine, DLT), or with a radioactive metal (111In). The biodistribution of a mixture of 125I (non-residualizing chloramine-T compared to residualizing DLT), 111In-labeled LL2 murine IgG2a or its fragments [F(ab′)2, Fab′], as well as its humanized, CDR-grafted form, was studied in nude mice bearing the RL human B-cell NHL cell line. Radiation
doses were calculated from the biodistribution data according to the Medical International Radiation Dose scheme to assess
the potential advantage for therapeutic applications. At all assay times, tumor uptake was higher with the residualizing labels
(i.e., 111In and DLT-125I) than with the non-residualizing iodine label. For example, tumor/blood ratios of 111In-labeled IgG were 3.2-, 3.5- and 2.8-fold higher than for non-residualizing iodinated IgG on days 3, 7 and 14, respectively.
Similar results were obtained for DLT-labeled IgG and fragments with residualized radiolabels. Tumor/organ ratios also were
higher with residualizing labels. No significant differences in tumor, blood and organ uptake were observed between murine
and humanized LL2. The conventionally iodinated anti-CD20 antibody, 1F5, had tumor uptake values comparable to those of iodinated
LL2, the uptake of both antibodies being strongly dependent on tumor size. These data suggest that, with internalizing antibodies
such as LL2, labeling with intracellularly retained isotopes has an advantage over released ones, which justifies further
clinical trials with residualizing 111In-labeled LL2 for diagnosis, and residualizing 131I and 90Y labels for therapy.
Received: 23 August 1996 / Accepted: 7 February 1997 相似文献
3.
Deyev SM Lebedenko EN 《BioEssays : news and reviews in molecular, cellular and developmental biology》2008,30(9):904-918
High-precision tumor targeting with conventional therapeutics is based on the concept of the ideal drug as a "magic bullet"; this became possible after techniques were developed for production of monoclonal antibodies (mAbs). Innovative DNA technologies have revolutionized this area and enhanced clinical efficiency of mAbs. The experience of applying small-size recombinant antibodies (monovalent binding fragments and their derivatives) to cancer targeting showed that even high-affinity monovalent interactions provide fast blood clearance but only modest retention time on the target antigen. Conversion of recombinant antibodies into multivalent format increases their functional affinity, decreases dissociation rates for cell-surface and optimizes biodistribution. In addition, it allows the creation of bispecific antibody molecules that can target two different antigens simultaneously and do not exist in nature. Different multimerization strategies used now in antibody engineering make it possible to optimize biodistribution and tumor targeting of recombinant antibody constructs for cancer diagnostics and therapy. 相似文献
4.
Photoimmunotherapy: treatment of animal tumors with tumor-specific monoclonal antibody-hematoporphyrin conjugates 总被引:9,自引:0,他引:9
D Mew C K Wat G H Towers J G Levy 《Journal of immunology (Baltimore, Md. : 1950)》1983,130(3):1473-1477
The term "photoimmunotherapy" describes an anti-cancer treatment that combines the phototoxic effects of chemical such as hematoporphyrin and the target-seeking ability of antibodies. Hematoporphyrin was chemically coupled to monoclonal antibodies directed to the DBA/2J myosarcoma M-1. Administration of anti-M-1-hematoporphyrin conjugates i.v. to M-1 tumor-bearing animals followed by exposure to incandescent light resulted in suppression of M-1 growth. The time interval between injection and light exposure was an important parameter in terms of tumor suppression. Tumor-bearing animals maintained in the dark for 96 to 196 hr after hematoporphyrin-antibody injection followed by 4-hr light exposure demonstrated significantly lower tumor incidence and longer latency periods, in comparison to conjugate-treated animals instantly exposed to light. The growth inhibiting properties of the conjugate appeared to be M-1-specific; it had no effect on the growth of a C57BL/6J lymphoma EL4. In addition, conjugates made with a nonspecific monoclonal antibody did not have any specific anti-tumor effect on M-1 growth. Treatment with equivalent doses of hematoporphyrin or antibody had no significant inhibiting effect on tumor growth. Clearly, the homing ability of the specific monoclonal antibody-hematoporphyrin conjugate was essential for effective drug delivery and inhibition of tumor growth. 相似文献
5.
Quantitation of the tumor-targeting properties of antibody fragments conjugated to cell-permeating HIV-1 TAT peptides 总被引:5,自引:0,他引:5
Niesner U Halin C Lozzi L Günthert M Neri P Wunderli-Allenspach H Zardi L Neri D 《Bioconjugate chemistry》2002,13(4):729-736
Human monoclonal antibodies are promising agents for the development of more selective anticancer therapeutics. However, the tumor-targeting efficiency of most anticancer antibodies is severely limited by their poor penetration into the tumor mass. Recent studies have shown that a peptide derived from the HIV TAT protein could improve the distribution of cytoplasmic reporter proteins when administered systemically as fusion proteins or cross-linked chimeras. In this article, we tested by quantitative biodistribtution analysis whether conjugation to TAT peptides could improve the tumor targeting properties of scFv(L19)-Cys: an engineered human antibody fragment specific for the ED-B domain of fibronectin, a marker located in the modified extracellular matrix surrounding tumor neovasculature. Our results show that TAT peptides, consisting either of L-amino acids or D-amino acids, can efficiently transduce target cells when conjugated to fluorophores and/or antibody fragments, suggesting a receptor-independent cell entry mechanism. However, conjugation of scFv(L19)-Cys to TAT peptides resulted in a severely reduced tumor targeting performance compared to the unconjugated antibody, as measured in murine F9 teratocarcinoma-bearing mice, after intravenous injection of the radiolabeled antibody preparations. Our results outline the usefulness of TAT peptides for the efficient in vitro transduction of cells with globular proteins. In particular, the use of TAT peptides composed of D-amino acids may significantly reduce proteolytic degradation. At the same time, the poor biodistribution properties of antibody-TAT conjugates cast doubts over the applicability of this methodology for the delivery of biopharmaceuticals in vivo. 相似文献
6.
Farley E. Yang Raya S. Brown Ken F. Koral Anaira C. Clavo Gayle A. Jackson Richard L. Wahl 《Cancer immunology, immunotherapy : CII》1992,35(6):365-372
Summary We studied the effect of monoclonal antibody protein dose on the uniformity of radioiodinated antibody distribution within tumor masses using quantitative autoradiography. Groups (n = 11–13/group) of athymic nude mice with subcutaneous HTB77 human ovarian carcinoma xenografts were injected intraperitoneally with an125I-labeled anticarcinoma-associated antigen murine monoclonal antibody, 5G6.4, using a high or a low protein dose (500 µg or 5 µg). At 6 days post-injection the macroscopic and microscopic intratumoral biodistribution of radiolabeled antibody was determined. The degree of heterogeneity of the labeled antibody distribution within each tumor was quantified and expressed as thecoefficient of variation (CV) of the activity levels in serial histological sections. Tumors from mice given the 500-µg protein doses had substantially lower CV values, 0.327±0.027, than did tumors from animals given 5-µg protein doses, 0.458±0.041, (P = 0.0078), indicating that the higher protein dose resulted in more homogeneous distribution of radioactivity in tumors than did the lower dose. While the percentage of the injected dose reaching the tumor was comparable between groups, injecting the higher dose of protein resulted in significantly lower tumor to non-tumor uptake ratios than those obtained for the lower protein dose. These data indicate, in this system, that to achieve more uniform intratumoral antibody (and radiation for radioimmunotherapy) delivery, a relatively high protein dose must be administered. However, to obtain this increased uniformity, a substantial drop in tumor/background uptake ratios was seen. Quantitative autoradiographic evaluation of human tumor xenografts is a useful method to assess the intratumoral distribution of antibodies. 相似文献
7.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1992,19(4):445-454
An improved method of direct labeling MAbs with 99mTc is described. Two murine monoclonal antibodies, designated Lym-1 and B72.3, have been successfully labeled with 99mTc in 0.1 M borate buffer at pH 9.3. The choice of buffer and pH was essential for obtaining a radiolabeling yield ⩾98%. In vitro studies demonstrated that the radiolabeled antibodies were stable and retained their immunoreactivity. Imaging and biodistribution studies using Raji and LS174T human tumor-bearing nude mice demonstrated a significant tumor uptake at 24-h post-injection of 99mTc-labeled MAbs. This improved labeling method showed better stability than those of previously published methods and resulted in significant improvement in the uptake of antibody in tumor. External images at 24 h post-injection revealed clearly visible tumors demonstrating the benefit of this method for tumor immunoscintigraphy. 相似文献
8.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1990,17(4):381-387
A monoclonal antibody against the murine T-cell antigen Thy 1.1 was radioiodinated using N-succin-imidyl p-iodobenzoate (PIP) in an attempt to decrease deiodination of the labeled antibody. The biodistribution of the PIP labeled antibody was compared to Iodogen labeled antibody in Thy 1.1+ lymphoma bearing AKR/Cum mice, where the antibody was tumor specific, and AKR/J mice where the antibody reacted with both tumor and normal T-cells. PIP labeling resulted in decreased iodine concentrations in stomach and salivary gland as compared to Iodogen labeling. There was little difference in radioiodine concentrations between the two preparations in tumor, lymphoid tissues or other organs. These results suggest deiodination of intact antibody plays little role in the clearance of radioiodinated anti-Thy 1.1 antibody from tissues. 相似文献
9.
Renner C Stehle I Lee FT Hall C Catimel B Nice EC Mountain A Rigopoulos A Brechbiel MW Pfreundschuh M Scott AM 《Cancer immunology, immunotherapy : CII》2001,50(2):102-108
Bispecific antibodies are currently being used in clinical trials in increasing numbers in the areas of breast cancer, prostate
cancer, non-Hodgkin's lymphoma and Hodgkin's lymphoma. We have previously performed two clinical trials in patients with Hodgkin's
disease with an anti-CD30/anti-CD16 bispecific antibody and demonstrated a 30% response rate in a cohort of patients otherwise
resistant to standard therapeutic modalities. However, no surrogate marker could be defined in these trials indicative of
optimal antibody dosing/scheduling or predictive for favorable response. In order to evaluate accurately the potential biodistribution
properties of bispecific antibody in patients, we have performed a detailed analysis of the binding properties and animal
model in vivo characteristics of these constructs. For this purpose, the parental antibodies (anti-CD30 and anti-CD16) and
the bispecific antibody (anti-CD30/anti-CD16) were radiolabeled with either 125I or 111In. Antibody integrity and binding properties after labeling were confirmed by Scatchard plot and Lindmo analysis. 111In-labeled antibodies revealed superior targeting properties in a standard SCID mouse tumor model. Both the bivalent parental
anti-CD30 monoclonal antibody and the monovalent anti-CD30/anti-CD16 bispecific antibody showed excellent uptake in CD30+ tumors which did not differ significantly between the two (maximum uptake 16.5% ± 4.2% vs. 18.4% ± 3.8% injected dose/gram
tissue). The equivalent targeting properties of the bispecific antibody compared with the parental anti-CD30 antibody encourages
the further clinical development of this bispecific antibody, and might help to explain the clinical responses seen with this
antibody so far in patients suffering from Hodgkin's disease.
Received: 26 October 2000 / Accepted: 15 December 2000 相似文献
10.
Tiepu Liu Donald J. Buchsbaum David T. Curiel Mohamed B. Khazaeli Ruby F. Meredith Albert F. LoBuglio 《Journal of molecular modeling》1996,2(12):467-477
A mathematical model simulation was performed to estimate the amount of radioactivity in plasma, normal tissues, and tumor tissue through three delivery approaches: one step radiolabeled monoclonal antibody (MAb) CC49 i.v. bolus injection, two step method with biotin conjugated CC49 i.v. bolus injection followed 72 hours later by i.v. bolus radiolabeled streptavidin injection, and gene therapy method to express biotin on the tumor cell surface followed by i.v. bolus radiolabeled streptavidin injection. The mathematical model was built based on a system of ordinary differential equations consisting of inputs and outputs of model components in plasma, normal tissues, and tumor tissue. Through computer modeling, we calculated concentrations of each component for plasma, tumor and normal tissues at various time points. Radioactivity ratios of tumor to plasma and tumor to normal tissues increased with time. The increase of tumor to normal tissue ratios was much faster for the gene therapy approach than for single step and two step approaches, e.g., a ratio of 24.26 vs. 2.06 and 6.24 at 72 hours after radioligand injection. Radioactivity ratios predicted by the model varied with the amount of radioactivity injected and the time interval between injections. The model could be used to evaluate different radioimmunotherapy strategies and to predict radioactivity biodistribution using other receptor-ligand systems. 相似文献
11.
Denise Karaoglu Hanzatian Annette Schwartz Farid Gizatullin Jamie Erickson Kangwen Deng Ruth Villanueva 《MABS-AUSTIN》2018,10(5):765-777
Therapeutic monoclonal antibodies and endogenous IgG antibodies show limited uptake into the central nervous system (CNS) due to the blood-brain barrier (BBB), which regulates and controls the selective and specific transport of both exogenous and endogenous materials to the brain. The use of natural transport mechanisms, such as receptor-mediated transcytosis (RMT), to deliver antibody therapeutics into the brain have been studied in rodents and monkeys. Recent successful examples include monovalent bispecific antibodies and mono- or bivalent fusion proteins; however, these formats do not have the capability to bind to both the CNS target and the BBB transport receptor in a bivalent fashion as a canonical antibody would. Dual-variable-domain immunoglobulin (DVD-Ig) proteins offer a bispecific format where monoclonal antibody-like bivalency to both the BBB receptor and the therapeutic target is preserved, enabling independent engineering of binding affinity, potency, valency, epitope and conformation, essential for successful generation of clinical candidates for CNS applications with desired drug-like properties. Each of these parameters can affect the binding and transcytosis ability mediated by different receptors on the brain endothelium differentially, allowing exploration of diverse properties. Here, we describe generation and characterization of several different DVD-Ig proteins, specific for four different CNS targets, capable of crossing the BBB through transcytosis mediated by the transferrin receptor 1 (TfR1). After systemic administration of each DVD-Ig, we used two independent methods in parallel to observe specific uptake into the brain. An electrochemiluminescent-based sensitive quantitative assay and a semi-quantitative immunohistochemistry technique were used for brain concentration determination and biodistribution/localization in brain, respectively. Significantly enhanced brain uptake and retention was observed for all TfR1 DVD-Ig proteins regardless of the CNS target or the systemic administration route selected. 相似文献
12.
M A Slinkin C Curtet C Sai-Maurel J F Gestin V P Torchilin J F Chatal 《Bioconjugate chemistry》1992,3(6):477-483
Polylysine-based chelating polymers were used for site-specific modification of anti-CEA mAb Fab' fragments via their SH group distal to the antigen-binding site of the antibody molecule. Conjugation was performed using chain-terminal (pyridyldithio)propionate or 4-(p-maleimidophenyl)butyrate moieties to form reducible (S-S) or stable (S-C) bonds between a polymer and Fab' molecule, respectively. One S-S conjugate (S-S9) and two different S-C conjugates (S-C3 and S-C9) were prepared using 3- and 9-kDa molecular weight polymers. No significant loss of immunoreactivity was observed in solid-phase immunoassay, 90-95% of 111In-labeled conjugates being bound to CEA-coated Sepharose beads. After labeling with 111In, the conjugates had a specific radioactivity of 90-120 microCi/micrograms. Injected in nude mice bearing LS 174T carcinoma, the conjugates produced different biodistribution patterns. S-S9 was practically unable to accumulate in tumor and produced very rapid blood clearance of radioactivity and high uptake of radioactivity in liver, spleen, and especially kidneys (225% ID/g 24 h postinjection). S-C3 and S-C9 produced practically the same blood clearances (much slower than that of S-S9) and significant tumor uptake (9-10% ID/g at 24 h). S-C3 gave significantly lower radioactivity in spleen, skin, and bones, and cleared more rapidly from liver and kidneys. Renal uptake for S-C3 and S-C9 was rather high (45% ID/g at 24 h), but much lower than for S-S9. 相似文献
13.
Magnus Essand P. Lögdahl Sten Nilsson Maria Wartenberg Helmut Acker J. Carlsson 《Cancer immunology, immunotherapy : CII》1996,43(1):39-43
Cellular retention and processing of a radiolabelled monoclonal anti-prostate antibody were evaluated after binding to prostatic
adenocarcinoma DU 145 cells. An endocytosis assay revealed that the rate of release of radioactivity from the cells had an
initially rapid phase within the first hours after antibody incubation, which was presumably due to release of monovalently
bound antibodies. This was followed by a slower phase, with the possible release of intact bivalently bound antibodies and
excretion of degraded internalized antibodies. The relative amount of released radioactivity of high molecular mass was high,
indicating that the major part of the antibodies were released without being internalized and degraded. However, when only
the radiolabelled antibody that remained cell-associated after 2 h and longer was considered, a substantial part was found
to be internalized and radioactive degradation products were excreted. About 30% of the initially cell-associated radioactivity
still remained associated with the cells after 48 h, indicating a rather slow antibody processing, which is favourable if
the antibody is to be used for targeted radiotherapy. The retention of cell-associated radioiodine was very similar irrespective
of whether the antibodies were radiolabelled with the direct chloramine-T method or the indirect ATE (succinimidyl based reagent)
method. Since the ATE method can be used to form stable antibody constructs with the therapeutically relevant alpha-emitting
radionuclide, astatine-211, this was an interesting finding that will be further evaluated in the future.
Received: 20 March 1996 / Accepted: 25 June 1996 相似文献
14.
Gabriel Gustafsson Fredrik Eriksson Christer Möller Tomás Lopes da Fonseca Tiago F. Outeiro Lars Lannfelt Joakim Bergström Martin Ingelsson 《Cellular and molecular neurobiology》2017,37(1):121-131
Immunotherapy targeting aggregated α-synuclein has emerged as a potential treatment strategy against Parkinson’s disease and other α-synucleinopathies. We have developed α-synuclein oligomer/protofibril selective antibodies that reduce toxic α-synuclein in a human cell line and, upon intraperitoneal administration, in spinal cord of transgenic mice. Here, we investigated under which conditions and by which mechanisms such antibodies can be internalized by cells. For this purpose, human neuroglioma H4 cells were treated with either monoclonal oligomer/protofibril selective α-synuclein antibodies, linear epitope monoclonal α-synuclein antibodies, or with a control antibody. The oligomer/protofibril selective antibody mAb47 displayed the highest cellular uptake and was therefore chosen for additional analyses. Next, α-synuclein overexpressing cells were incubated with mAb47, which resulted in increased antibody internalization as compared to non-transfected cells. Similarly, regular cells exposed to mAb47 together with media containing α-synuclein displayed a higher uptake as compared to cells incubated with regular media. Finally, different Fcγ receptors were targeted and we then found that blockage of FcγRI and FcγRIIB/C resulted in reduced antibody internalization. Our data thus indicate that the robust uptake of the oligomer/protofibril selective antibody mAb47 by human CNS-derived cells is enhanced by extracellular α-synuclein and mediated via Fcγ receptors. Altogether, our finding lend further support to the belief that α-synuclein pathology can be modified by monoclonal antibodies and that these can target toxic α-synuclein species in the extracellular milieu. In the context of immunotherapy, antibody binding of α-synuclein would then not only block further aggregation but also mediate internalization and subsequent degradation of antigen–antibody complexes. 相似文献
15.
B. Desrues B. Collet M. P. Ramé D. Bourel P. Bourguet A. Martin P. Delaval L. Toujas L. Dazord 《Cancer immunology, immunotherapy : CII》1989,30(5):295-299
Monoclonal antibody Po66, produced by immunization against a patient's lung squamous cell carcinoma was found suitable for the scintigraphic detection of human tumours. Surprisingly, the cellular antigen recognized by Po66 was abundant in the cytoplasm of tumour cells but could not be detected on the surface membrane. In the present work the biodistribution of radiolabelled Po66 and of an unrelated immunoglobulin were studied comparatively after intravenous injection into nude mice bearing lung squamous cell carcinoma grafts. Radioactivity distribution among mouse organs and tumour was analysed by gamma counting and autohistoradiography. After injection, radiolabelled Po66 decreased rapidly from the blood in tumour-bearing animals whereas, in controls, it remained at a level comparable to that of the unrelated immunoglobulin. The antibody seemed slowly trapped by the tumour and, 12 days after its injection, distribution ratios between tumour and mouse organs reached values of 20-30 as against 1 in animals injected with the non-specific immunoglobulin. Autohistoradiographic investigations in the tumour confirmed the slow diffusion rate of the antibody, which remained in the vascular spaces up to the 24th hour after injection and diffused afterwards throughout the clusters of tumor cells. Furthermore, radioactivity was detected in cells which, unexpectedly, seemed morphologically unaltered. These cells, the viability of which remains to be determined, were predominant in the central area of the tumours. The results presented constitute new evidence of the ability of an in vivo injected monoclonal antibody to reach a cytoplasmic target inside non-necrotic cells and suggest that the cells permeable to the antibody might be in defective nutritional conditions. 相似文献
16.
Baptiste Gouyou Tiziano Ongaro Samuele Cazzamalli Roberto De Luca Anne Kerschenmeyer Philippe Valet Alessandra Villa Dario Neri Mattia Matasci 《Experimental biology and medicine (Maywood, N.J.)》2021,246(8):940
Interleukin-9 is a cytokine with multiple functions, including the ability to activate group 2 innate lymphoid cells, which has been postulated to be therapeutically active in mouse models of arthritis. Similarly, interleukin-9 has been suggested to play an important role in tumor immunity. Here, we describe the cloning, expression, and characterization of three fusion proteins based on murine interleukin-9 and the F8 antibody, specific to the alternatively spliced EDA domain of fibronectin. EDA is strongly expressed in cancer and in various arthritic conditions, while being undetectable in the majority of healthy organs. Interleukin-9-based fusion proteins with an irrelevant antibody specific to hen egg lysozyme served as negative control in our study. The fusion proteins were characterized by quantitative biodistribution analysis in tumor-bearing mice using radioiodinated protein preparations. The highest tumor uptake and best tumor:organ ratios were observed for a format, in which the interleukin-9 moiety was flanked by two units of the F8 antibody in single-chain Fv format. Biological activity of interleukin-9 was retained when the payload was fused to antibodies. However, the targeted delivery of interleukin-9 to the disease site resulted in a modest anti-tumor activity in three different murine models of cancer (K1735M2, CT26, and F9), while no therapeutic benefit was observed in a collagen induced model of arthritis. Collectively, these results confirm the possibility to deliver interleukin-9 to the site of disease but cast doubts about the alleged therapeutic activity of this cytokine in cancer and arthritis, which has been postulated in previous publications. 相似文献
17.
Sridhar Nimmagadda Mrudula Pullambhatla Ala Lisok Chaoxin Hu Anirban Maitra Martin G Pomper 《Biochemical and biophysical research communications》2014
The receptor tyrosine kinase Axl is overexpressed in and leads to patient morbidity and mortality in a variety of cancers. Axl–Gas6 interactions are critical for tumor growth, angiogenesis and metastasis. The goal of this study was to investigate the feasibility of imaging graded levels of Axl expression in tumors using a radiolabeled antibody. We radiolabeled anti-human Axl (Axl mAb) and control IgG1 antibodies with 125I with high specific radioactivity and radiochemical purity, resulting in an immunoreactive fraction suitable for in vivo studies. Radiolabeled antibodies were investigated in severe combined immunodeficient mice harboring subcutaneous CFPAC (Axlhigh) and Panc1 (Axllow) pancreatic cancer xenografts by ex vivo biodistribution and imaging. Based on these results, the specificity of [125I]Axl mAb was also validated in mice harboring orthotopic Panc1 or CFPAC tumors and in mice harboring subcutaneous 22Rv1 (Axllow) or DU145 (Axlhigh) prostate tumors by ex vivo biodistribution and imaging studies at 72 h post-injection of the antibody. Both imaging and biodistribution studies demonstrated specific and persistent accumulation of [125I]Axl mAb in Axlhigh (CFPAC and DU145) expression tumors compared to the Axllow (Panc1 and 22Rv1) expression tumors. Axl expression in these tumors was further confirmed by immunohistochemical studies. No difference in the uptake of radioactivity was observed between the control [125I]IgG1 antibody in the Axlhigh and Axllow expression tumors. These data demonstrate the feasibility of imaging Axl expression in pancreatic and prostate tumor xenografts. 相似文献
18.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1986,13(4):347-352
Site-specific modification of monoclonal antibodies at their oligosaccharide had previously been demonstrated to produce excellent 111In imaging in a xenograft model using a Brown Norway (BN) rat lymphoma and a rat anti-BN MHC monoclonal antibody [Lee C. et al. Fed. Proc. Abstr. 43 3014 (1984)]. These results are due, in part, to lack of liver uptake, so we wanted to evaluate the extent of hepatic uptake observed with different monoclonal antibodies in normal mice. Biodistribution data were obtained for four monoclonal antibodies by first modifying each antibody at its carbohydrate with a diethylenetriaminepentaacetic acid (DTPA) derivative. The antibodies were then labelled with 111In and injected into normal mice. Images were obtained 24 h post-injection, and at 48 h the mice were dissected and the tissue-to-blood (T:B) ratios determined. T:B ratios were approximately 1 (or less) for every organ evaluated, indicating minimal non-specific uptake into these organs. Data is also presented for the BN-rat system which shows excellent localization into the tumor xenograft and low non-specific organ uptake. These data indicate that modification of antibodies site-specifically at their oligosaccharide results in minimal non-specific uptake into non-target tissues and enhanced localization into the tumor target, and that this may represent a preferred method for production of 111In labelled antibodies. 相似文献
19.
Localization of monoclonal antibody TNT-1 in experimental kidney infarction of the mouse 总被引:1,自引:0,他引:1
An experimental kidney infarction model was developed in the mouse to study the uptake of a radiolabeled monoclonal antibody previously shown to bind to degenerating cells in malignant tumors. To determine if this approach is applicable to normal tissue and cell degeneration, kidney infarction was produced by clamping the mouse renal artery for 3 h using surgical procedures. Various groups of mice were injected with 131I-labeled TNT-1 F(ab')2 monoclonal antibody directed against nuclear histone antigens at varying intervals after surgery. Imaging, biodistribution, autoradiography, and histological studies were performed on each group of mice, including sham-operated controls, to quantitate the level of binding and localize the uptake of label in clamped and unclamped (contralateral) kidneys. As additional controls, clamped mice were administered radiolabeled irrelevant monoclonal antibody Lym-1 or mouse albumin. The results showed a marked selective uptake of radiolabeled TNT-1 F(ab')2 in the injured clamped kidney compared with the untreated kidney and other normal organs of the mouse. These studies define a model of normal organ necrosis that may be useful for study of the kinetics of antibody uptake in infarcted tissues. 相似文献
20.
R M Nakamura 《Clinical physiology and biochemistry》1983,1(2-5):160-172
Kohler and Milstein have shown that individual clones of normal antibody-secreting lymphocytes could be immortalized by fusion with myeloma cells. These investigators initiated a new era of technology with the successful in vitro production of monoclonal antibodies via somatic cell hybridization. With the use of monoclonal antibodies, many major problems arising from the limited specificity and reproducibility of conventional antisera can be solved. Some of the commonly employed methods for the production of monoclonal antibody are: (1) fusion of sensitized lymphocytes and myelomas from different sources to produce continuous antibody-producing cell lines; (2) in vitro viral transformation of sensitized lymphocytes to form continuous antibody-producing cells; (3) hybrid fusion of sensitized lymphocytes and continuous B lymphocyte cell lines. During the past few years, monoclonal antibody methodology has been used in almost every area of biological research. Monoclonal antibodies have been used as structural probes for proteins and hormones, and as highly specific agents for histocompatibility testing, tumor localization, immunotherapy, purification of molecules, identification of new surface antigens on lymphocytes and tumor cells, and detection of drug levels and microbial and parasitic diseases. In addition, several investigators have developed alternative methods for the production of human as well as mouse and rat monoclonal antibodies. The new technology of in vitro production of animal and human monoclonal antibodies will have many future applications in diagnosis and therapy in laboratory and clinical medicine. 相似文献