RESUMO
STUDY DESIGN: Cell transplantation strategies are gaining increasing interest for spinal cord injury (SCI) with the objective of promoting spinal cord repair. To avoid allogenic graft rejection, an adequate immune suppression is required, and one of the most potent and commonly used immunosuppressives is cyclosporin A (CsA). In SCI, permanent sensory motor loss is combined with modifications of drug absorption, distribution and elimination. OBJECTIVES: The objectives of this study were to thoroughly explore histological and functional outcomes of CsA treatment in a rat model of spinal cord compression. SETTING: Experiments were carried out at the Institute for Neurosciences of Montpellier (France), the Integrative Biology of Neurodegeneration Laboratory (Spain) and in the Novartis Institutes for BioMedical Research (Switzerland) for CsA blood concentration determination. METHODS: We first evaluated histological outcomes of CsA treatment on kidneys and spinal cord after SCI. We then investigated whether SCI modified CsA blood concentration. Finally, using behavioral analysis, we assessed the potential CsA impact on functional recovery. RESULTS: When spinal-cord-injured rats were treated with a CsA dose of 10 mg kg(-1) per day, we observed deleterious effects on kidneys, associated with modifications of CsA blood concentration. Adding an antibiotic treatment reduced kidney alteration without modifying CsA blood concentration. Finally, we showed that CsA treatment per se modified neither functional recovery nor lesion extension. CONCLUSION: This study pinpoints the absolute requirement of careful CsA monitoring in the clinical setting for patients with SCI to minimize potential unexpected effects and avoid therapeutic failure.
Assuntos
Transplante de Células/métodos , Ciclosporina/toxicidade , Rejeição de Enxerto/tratamento farmacológico , Nefropatias/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Transplante de Células/efeitos adversos , Ciclosporina/sangue , Ciclosporina/uso terapêutico , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Rejeição de Enxerto/fisiopatologia , Rejeição de Enxerto/prevenção & controle , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Imunossupressores/toxicidade , Nefropatias/induzido quimicamente , Masculino , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/cirurgia , Resultado do TratamentoRESUMO
Radioimmunoconjugates of 170H.82 (m170), a panadenocarcinoma monoclonal antibody, are effective for imaging primary and metastatic breast cancer. To evaluate m170 as a targeting agent for therapy, we developed (111)In- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10 tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-m170 immunoconjugates with 99% purity by molecular sieving and immunoreactivity comparable to unmodified antibody. (111)In-m170 pharmacokinetic studies were performed prior to each therapy to determine the maximum dose of 90Y-m170 that could be administered without exceeding a limit of 800 rad to the liver, lungs, or kidneys or 250 rad to the whole body or bone marrow for each of three cycles of treatment. Peripheral blood stem cells (PBSCs) were harvested and cyclosporin A (5 mg/kg twice daily) was administered as strategies to ameliorate myelosuppression and prevent the development of HAMA, respectively. An (111)In imaging/pharmacokinetic study was performed, and the 90Y dose was calculated and administered. The liver was the 90Y dose-limiting organ. The mean and range of calculated doses (in rad/mCi) for the five patients evaluated were as follows: whole body, 2.3 (2.1-2.4); liver, 17.8 (12.7-22.2); lung, 6.4 (4.8-7.2); kidney, 6.9 (6.3-11.5); marrow, 3.6 (1.9-4.4); and tumors (n = 25), 71.5 (14.1-141.5). Of the three patients treated, with doses of 37, 54, and 57 mCi of 90Y, one had a partial response, one had measurable tumor reduction but less than a partial response, and one had stable disease for more than 1 month. PBSCs prevented prolonged myelosuppression. The therapeutic responses, coupled with an absence, thus far, of significant adverse sequelae, suggest that this dosimetry-based approach combined with PBSCs may lead to effective therapy when higher 90Y doses are reached.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/terapia , Ciclosporina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Radioimunoterapia , Dosagem Radioterapêutica , Radioisótopos de Ítrio/uso terapêutico , Adulto , Animais , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Transplante AutólogoRESUMO
The labeling of a monoclonal antibody K-1-21 with 153Sm has been investigated using the bifunctional chelate cyclic diethylenetriaminepentaacetic acid (DTPA) anhydride. Labeling efficiencies greater than 60% were obtained using high specific activity [153Sm]chloride and a cDTPAa:MAb conjugation ratio of 20:1. The resultant labeled antibody had a s.a. greater than 150 MBq.mg-1 and a % retained immunoreactivity greater than 90%. Imaging and biodistribution studies in a rat model demonstrated that specific uptake of 153Sm-K-1-21 into s.c. implants of the target antigen could be clearly detected in scintigrams at 6 days p.i. The specific uptake (1.90 +/- 0.45% ID/g, 19.95 +/- 2.20 Implant:Blood ratio) compared favorably to 131I- and 111In-labeled K-1-21 (2.52 +/- 0.20 and 3.33 +/- 0.20% ID/g, 7.69 +/- 0.45 and 10.10 +/- 0.60 I:B, respectively). Labeling of MAbs with 153Sm for combined scintigraphy/therapy is feasible at clinically appropriate specific activities using cDTPAa, with the resultant conjugates retaining immunoreactivity and in vivo antigen localization.
Assuntos
Anticorpos Monoclonais , Radioisótopos , Samário , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Imunoglobulina G/metabolismo , Imunoglobulina G/uso terapêutico , Imunotoxinas/metabolismo , Imunotoxinas/uso terapêutico , Radioisótopos de Índio/metabolismo , Radioisótopos de Índio/uso terapêutico , Radioisótopos do Iodo/metabolismo , Radioisótopos do Iodo/uso terapêutico , Masculino , Ácido Pentético/farmacocinética , Ácido Pentético/uso terapêutico , Radioisótopos/metabolismo , Radioisótopos/uso terapêutico , Ratos , Ratos Endogâmicos F344 , Samário/metabolismo , Samário/uso terapêutico , Fatores de Tempo , Distribuição TecidualRESUMO
Intravenously administered peanut lectin (PNA), iodinated with 131I ([131I]PNA), is rapidly cleared from the plasma by the kidneys in dogs (clearance [total body] = 17.52 +/- 8.74 ml/min). Dynamic gamma camera renal scintigraphy demonstrated renal accumulation and excretion phases of the [131I]PNA renogram in dogs and rabbits (% injection dose-at-peak = 21.8 +/- 3.3% and 19.6 +/- 4.3%, time-to-peak = 44.6 +/- 4.8 min and 37.2 +/- 6.9 min, respectively). Immunoperoxidase staining of kidney sections, following i.v. administered PNA, demonstrated predominant accumulation by the proximal tubules of mice, rabbits, and dogs. The basement membrane was intensely stained at early times p.i. while intracellular and luminal PNA was evident within 1 hr. Urine analysis confirmed the presence of intact [131I]PNA in the bladder contents, while protein degradation products, and a small percentage of the free iodide (less than 5%) were noted within 1 hr p.i. The relative proportion of free iodide increased at later times p.i. (greater than 6 hr). A receptor mediated excretion mechanism is proposed for the clearance of PNA and may be useful for the study of renal tubular function.
Assuntos
Radioisótopos do Iodo , Túbulos Renais/diagnóstico por imagem , Rim/metabolismo , Lectinas , Receptores Mitogênicos/metabolismo , Animais , Cães , Técnicas Imunoenzimáticas , Radioisótopos do Iodo/sangue , Radioisótopos do Iodo/metabolismo , Córtex Renal/metabolismo , Cinética , Lectinas/sangue , Lectinas/metabolismo , Masculino , Camundongos , Aglutinina de Amendoim , Coelhos , Ensaio Radioligante , Cintilografia , Bexiga Urinária/metabolismoRESUMO
UNLABELLED: Previous studies have shown high accuracy for immunoscintigraphy with 99mTc-MAb-174 in patients with squamous-cell carcinoma of the head and neck region compared to CT and MRI. We conducted a prospective study to determine if immunoscintigraphy provides additional diagnostic information for radiation treatment planning. METHODS: Radioimmunoscintigraphy (RIS) was performed on 40 patients (planar, whole-body, SPECT) with histologically confirmed squamous-cell carcinoma (30 primary tumors, 10 recurrences) after injection of the 99mTc (1.1 GBq) labeled monoclonal anti-squamous-cell cancer antibody 174H0.64 (murine IgG1). Results were combined with information obtained by clinical examination, sonography, panendoscopy and x-ray CT. The strategy for radiation treatment and the required treatment volumes were defined with and without immunoscintigraphical findings. RESULTS: Additional diagnostically relevant information from RIS was obtained from 10 patients (25%) with advanced tumors or recurrences. In three patients (7.5%), the treatment volume had to be extended. The therapeutic strategy for seven patients (17.5%) had to be changed due to the detection of metastatic disease beyond the head and neck region. RIS of patients with squamous-cell cancers of the head and neck region with 99mTcMAb-174H0.64 enabled the detection of tumors that were not depicted by other conventional diagnostic imaging procedures. CONCLUSION: The use of RIS in radiation treatment planning of advanced tumors of the head and neck region appears to yield important diagnostic information that may alter patient management.
Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/radioterapia , Radioimunodetecção , Tomografia Computadorizada de Emissão de Fóton Único , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , TecnécioRESUMO
Injection of 99mTc-labeled Fab' fragments of the anti-fibrin antibody DD-3B6/22, in the baboon, resulted in clear visualisation of both fresh and aged autologous thrombi by gamma scintigraphy. Whole body scintigraphy, pharmacokinetics and urine analysis showed rapid renal excretion of the conjugate with little accumulation of label in other organs. 99mTc-DD-3B6/22 Fab' appears a suitable candidate for further investigation as a radioimaging agent for thrombi in humans.
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/imunologia , Fragmentos Fab das Imunoglobulinas , Tecnécio , Trombose/diagnóstico , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Papio , Flebografia , Radioimunodetecção , Tecnécio/farmacocinética , Trombose/metabolismoRESUMO
The D Dimer (DD) site formed by linkage of D domains from adjacent fibrin (FN) molecules is unique to cross-linked FN and its degradation products and is not found in FN monomer or fibrinogen (FB). Thus monoclonal antibodies (MAb) reactive to DD should have a very suitable specificity for in vivo thrombus detection. Two anti-DD MAbs have been labelled with 131-I and assessed as scintigraphic agents in a normal rat model system. Each rat received 3 sc implants of antigen covalently coupled to Sepharose beads: 1) Human DD 2) Human FB 3) Glycine (GL) (control). Scintigraphic images taken 7 days after injection of 131-I anti DD MAb showed clear localisation of both anti-DD MAbs to the DD implant rather than to the FB or GL implants with no localisation in normal tissues. This was confirmed in biodistribution studies. Injection of anti-DD MAbs DD-3B6/22 and DD-IC3/108 resulted in DD: blood ratios of 10.4 +/- 0.6 and 4.9 +/- 0.3 respectively. These results suggest that anti-DD MAbs will have potential for thrombus radioimmunodetection.
Assuntos
Anticorpos Monoclonais , Fibrina/imunologia , Trombose/diagnóstico por imagem , Animais , Sítios de Ligação de Anticorpos , Modelos Animais de Doenças , Implantes de Medicamento/administração & dosagem , Feminino , Fibrinogênio/administração & dosagem , Humanos , Radioisótopos do Iodo , Masculino , Cintilografia , Ratos , Ratos Endogâmicos F344 , Trombose/metabolismo , Distribuição TecidualRESUMO
UNLABELLED: PURPOSE. This article reports the pharmacokinetics, radiation dosimetry and radioimmunoscintigraphy (RIS) of two (99m)Tc-labelled monoclonal antibodies (MAb) used to detect cancer. METHODS: The effects of circulating antigen in female cancer patients are explored and their effects on the ability of these MAbs to effectively perform as RIS agents noted. To illustrate the effects of circulating antigen, data using MAb B43.13 (OVAREX, AltaRex Corp., Waltham, MA, USA) from a Pilot study in ovarian cancer patients are presented. The results from a Phase II study of MAb 170H.82 (Tru-Scint AD, BIOMIRA INC., Edmonton, Alberta, Canada) in patients with primary and locally recurrent breast cancer were used to portray the biodistribution patterns when no circulating antigen is present. Data from planar gamma camera images were obtained for both groups and used for pharmacokinetic and radiation dosimetry analyses. RESULTS: A pharmacokinetic analysis indicated a shorter residence time and higher clearance of (99m)Tc-MAb-B43.13 that was ascribed in part to the circulating CA 125 antigen in this group of ovarian cancer patients. CONCLUSION: These clearance patterns resulted in acceptable, though higher radiation doses to the spleen and urinary bladder wall for these patients when compared to the MAb-170H.82 group. Both MAbs were found to produce acceptable radioimmunoscintigraphic images
Assuntos
Adenocarcinoma/metabolismo , Anticorpos Monoclonais/farmacocinética , Neoplasias da Mama/metabolismo , Antígeno Ca-125/sangue , Compostos de Organotecnécio/farmacocinética , Neoplasias Ovarianas/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/imunologia , Adulto , Idoso , Anticorpos Monoclonais Murinos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/imunologia , Antígeno Ca-125/imunologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Cintilografia , Distribuição TecidualRESUMO
Radioimmunoscintigraphy (RIS) with Tc-99m labeled 170H.82, an intact murine monoclonal antibody (MAb) was performed in 27 patients with suspected primary, recurrent, or metastatic breast cancer. For radioimmunoimaging the authors used a double-headed, high-resolution gamma camera. The lesions detected by RIS were evaluated by histopathology, and for metastatic disease by CT, MRI, and bone scan. If the evaluation was made lesion by lesion, RIS with Tc-99m MAb 170H.82 showed 23 true-positive results, 3 false-negative results, 9 true-negative results, 3 false-positive results for primary and recurrent disease; sensitivity was 88% and specificity was 75%. In patients with distant metastases, detection rate was 67% (12 true-positive results and 6 false-negative results). All patients had normal baseline values for human anti-mouse antibodies (HAMA) and 6 weeks after RIS with 2 mg MAb, only 2 of 23 patients had developed a HAMA response (9%). No adverse effects were observed. The authors' clinical experience shows that RIS with MAb 170H.82 is a valuable additional method for detecting breast cancer, especially in patients with uncertain primaries or scar tissue after breast conserving treatment in which differential diagnosis is very difficult.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Radioimunodetecção , Tecnécio , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Feminino , Câmaras gama , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios XRESUMO
The prognosis of patients surviving myocardial infarction is influenced by a high early mortality rate. The aim of this study was to assess the prognostic value of cardiac catheterisation and coronary angiography performed early after infarction to identify patients at high risk. Two hundred patients including 10 women with an average age of 49.1 +/- 8.6 years surviving (greater than 1 month) primary myocardial infarction underwent haemodynamic and coronary angiographic investigations on average 26 days after the onset of infarction (26 +/- 17 days, range 1 to 90 days). All patients were followed up for average period of 43.2 +/- 13.3 months. The overall mortality rate was 13.5% (27/200). The commonest cause of demise was sudden death: 52% (14/27). Most patients died within the first year of infarction (11/27). Indices of left ventricular function (left ventricular end diastolic pressure and ejection fraction) were significantly more pathological in the patients who died. Similarly, there were many more patients with multivessel (93%) and triple vessel disease (63%) in this sub group (p less than 0,001). Analysis of actuarial survival with respect to ejection fraction demonstrated the prognostic importance of this factor, especially during the first year: 38.5% mortality in patients with ejection fractions below 30%. Triple vessel disease was associated with 13% mortality in the first year. When these two factors were combined, the risk of death in the first year was 50%, so identifying a very high risk subgroup. On the other hand, no deaths were observed in patients with a single coronary lesion and normal left ventricular function (ejection fraction greater than 50%) during 72 months follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Infarto do Miocárdio/diagnóstico , Adulto , Idoso , Angiocardiografia , Cateterismo Cardíaco , Feminino , Seguimentos , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/mortalidade , Prognóstico , RiscoRESUMO
Serotonergic innervation of the spinal cord in mammals has multiple roles in the control of motor, sensory and visceral functions. In rats, functional consequences of spinal cord injury at thoracic level can be improved by a substitutive transplantation of serotonin (5-HT) neurons or regeneration under the trophic influence of grafted stem cells. Translation to either pharmacological and/or cellular therapies in humans requires the mapping of the spinal cord 5-HT innervation and its receptors to determine their involvement in specific functions. Here, we have performed a preliminary mapping of serotonergic processes and serotonin-lA (5-HT(1A)) receptors in thoracic and lumbar segments of the human spinal cord. As in rodents and non-human primates, 5-HT profiles in human spinal cord are present in the ventral horn, surrounding motoneurons, and also contact their presumptive dendrites at lumbar level. 5-HT(1A) receptors are present in the same area, but are more densely expressed at lumbar level. 5-HT profiles are also present in the intermediolateral region, where 5-HT(1A) receptors are absent. Finally, we observed numerous serotonergic profiles in the superficial part (equivalent of Rexed lamina II) of the dorsal horn, which also displayed high levels of 5-HT(1A) receptors. These findings pave the way for local specific therapies involving cellular and/or pharmacological tools targeting the serotonergic system.
Assuntos
Receptor 5-HT1A de Serotonina/metabolismo , Neurônios Serotoninérgicos/citologia , Medula Espinal/anatomia & histologia , Adolescente , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Neurônios Serotoninérgicos/metabolismo , Medula Espinal/metabolismo , Adulto JovemAssuntos
Anticorpos Anti-Idiotípicos/biossíntese , Anticorpos Heterófilos/biossíntese , Anticorpos Monoclonais/imunologia , Neoplasias Ovarianas/imunologia , Adulto , Antígenos Glicosídicos Associados a Tumores , Cistadenocarcinoma Papilar/diagnóstico por imagem , Cistadenocarcinoma Papilar/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/diagnóstico por imagem , Radioimunodetecção , Taxa de Sobrevida , Tomografia Computadorizada por Raios XAssuntos
Nefropatias/diagnóstico por imagem , Adolescente , Adulto , Criança , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Ácido Pentético , Doses de Radiação , Cintilografia , Succímero , Tecnécio , Ácido Dimercaptossuccínico Tecnécio Tc 99m , Pentetato de Tecnécio Tc 99m , Ureter , Cateterismo UrinárioAssuntos
Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Infecções Fúngicas do Sistema Nervoso Central/tratamento farmacológico , Imunossupressores/efeitos adversos , Interferon gama/uso terapêutico , Transplante de Fígado , Adulto , Aspergilose/microbiologia , Infecções Fúngicas do Sistema Nervoso Central/microbiologia , Quimioterapia Combinada , Humanos , Masculino , Resultado do TratamentoRESUMO
Transferrin is essential for the entry of iron into cells, but whether the entire iron-transferrin complex or only the iron enters is not known. Separation of the cellular from the interparticulate radioactivity is a common problem with such studies. By pelleting cells under oil, we have made precise measurements of the uptake capacity for 59Fe of mouse lymphoma RI cells. At 37 degrees C an 18-fold concentration of iron was observed within 30 min; at 0 degrees C this value was about 3-fold. At 37 degrees C a maximum of 18,000 molecules of 125I-labelled Fe-transferrin were bound to each cell; this was reduced by about half at 0 degrees C. At 37 degrees C about 10,000-12,000 binding sites for 125I-apotransferrin were detected on each cell. From our data we conclude that although essential for the transport of iron, it is unlikely that transferrin enters RI cells. It is possible that iron is actively transported and that the receptor population is heterogeneous.
Assuntos
Apoproteínas , Ferro/metabolismo , Linfoma/metabolismo , Transferrina/metabolismo , Animais , Linhagem Celular , Radioisótopos do Iodo , Radioisótopos de Ferro , Cinética , Linfoma/patologia , CamundongosRESUMO
Fifty-three women with clinical evidence of adenocarcinoma of the breast were studied with technetium-99m labelled monoclonal antibody (MAb) 170H.82 at protein doses of 1, 2 and 4 mg. An overall per lesion efficacy of 83.5% sensitivity and 97.7% positive predictive value was obtained. Efficacy appears higher in lesions restricted to the breast and local regional disease than systemic metastases. For the 2 mg dose the breast/local regional disease efficacy was 90% sensitivity and 90.2% positive predictive value. The biodistribution of this MAb was best represented by a two-compartment model with a distribution-phase half-life of 4.0+/-1.4 h, followed by an elimination-phase half-life of 39.6+/-6.6 h. In all six patients studied, the critical organ was the kidney, with a mean radiation absorbed dose of 37+/-6.9 mGy/GBq. The accuracy of this imaging technique allows the development of diagnostic strategies for the routine use of the compound in patients with breast cancer.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , Radioimunodetecção , Tecnécio , Feminino , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Doses de Radiação , Sensibilidade e Especificidade , Distribuição TecidualRESUMO
Samarium-153 (153Sm) radioimmunoconjugates of the monoclonal antibody K-1-21 were produced using the bifunctional chelate 2-(p-isothiocyanatobenzyl)-6- methyldiethylenetriaminepentaacetic acid (Mx-DTPA). The specific activity (up to 150 MBq mg-1) and percent retained immunoreactivity (greater than 75%) were similar to that of 153Sm-K-1-21 conjugates formed with cyclic DTPA anhydride (cDTPAa). In vivo biodistribution studies showed specific localization of 153Sm-Mx-DTPA-K-1-21 to target antigen implants and higher blood pool and lower uptake in liver, spleen, kidney, and bone when compared to 153Sm-cDTPAa-K-1-21. The improved in vivo distribution of 153Sm-Mx-DTPA-K-1-21 should result in lower radiotoxicity to nontarget tissues when used for radioimmunotherapy purposes.
Assuntos
Anticorpos Monoclonais , Ácido Pentético/análogos & derivados , Ácido Pentético/química , Radioisótopos , Samário , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Marcação por Isótopo , Masculino , Ratos , Ratos Endogâmicos F344 , Distribuição TecidualRESUMO
The antifibrin DD-3B6/22 monoclonal antibody Fab' fragment, a murine immunoglobulin, IgG3, has been labelled with technetium-99 m (99mTc) via a transchelation reaction, to specific activity in excess of 30 mCi/mg protein. The radiolabelling of Fab' was dependent on time, temperature, pH, antibody concentrations and nature of intermediary transchelation complex used. The resultant radioconjugate was stable in vitro and in vivo. Blood clearance of 99mTc-Fab' in rat followed two compartment kinetics with the half time of the fast phase being 0.5 h. The main route of excretion was via the kidneys with little uptake indicated by other tissues. The results suggest that the inherent specificity of the antibody, small molecular size, rapid plasma clearance, high specific radioactivity, together with the physical properties of the 99mTc label, combine to make this labelled monoclonal antibody (MoAb), potentially suitable as a radiopharmaceutical for the scintigraphic detection of thrombi in humans.
Assuntos
Anticorpos Monoclonais , Fibrina/imunologia , Tecnécio , Trombose/diagnóstico , Animais , Estudos de Avaliação como Assunto , Fragmentos Fab das Imunoglobulinas , Camundongos , Ratos , Ratos Wistar , Tecnécio/farmacocinética , Distribuição TecidualRESUMO
The detection of thrombi in rabbits has been investigated with 131I-labelled DD-3B6/22, a monoclonal antibody (Mab) reactive at high affinity (Kd = 2.68 x 10(-10) M) with human D Dimer (DD). DD-3B6/22 bound well to both "fresh" and "aged" human clots in an in vitro assay but showed poor binding to rabbit clots. However, reactivity was restored to rabbit blood if it was seeded, before clotting, with human DD covalently coupled to Sepharose beads. Thus, a rabbit model was developed in which blood was allowed to clot around DD-Sepharose beads introduced into the jugular vein. Gamma camera imaging showed that intact 131I-labelled DD-3B6/22 localised to these clots within 24 h. Uptake at this time was 0.202 +/- 0.012% injected dose per gram (%ID/g) compared with 0.086 +/- 0.018%ID/g after injection of control antibody. 131I-labelled F(ab')2 fragments of DD-3B6/22 allowed earlier scintigraphic detection of the clot which was evident 4 h after injection. Uptake in the clot at 24 h was 0.154 +/- 0.038 %ID/g compared with 0.109 +/- 0.027 %ID/g for a control F(ab')2. As antigen levels in the clot are estimated to be less than 300 micrograms DD, thus representing a very small human clot, the DD-3B6/22 Mab would appear to have a good potential for the sensitive detection of thrombi in a clinical setting.
Assuntos
Anticorpos Monoclonais , Fibrina/imunologia , Radioisótopos do Iodo , Trombose/diagnóstico por imagem , Animais , Feminino , Masculino , Coelhos , CintilografiaRESUMO
Peanut lectin (PNA) has been shown to have a high affinity for Thomsen-Friedenreich (T) antigen, which is associated with the membrane of many solid tumour cells. PNA labelled with 131I was used as a tumour-imaging substance in patients with known metastatic cancer. Serial gamma scintiscans were obtained in 17 patients following a single injection of 131I-labelled PNA. Only in 1 patient was this technique able to reveal a known metastasis at analogue imaging. In the remaining patients, no visible uptake of 131I-PNA could be demonstrated at sites of known metastases. PNA is rapidly excreted through the kidneys and localizes in the renal tubules. As a tumour-imaging agent, 131I-PNA appears to be without value, but its renal-excretory characteristics make it a potentially useful agent for the in vivo assessment of renal-tubular disorders.