Conformational Correction Mechanisms Aiding Antigen Recognition by a Humanized Antibody

The crystal structure of the complex between hen egg lysozyme and the Fv fragment of a humanized antilysozyme antibody was determined to 2.7-Å resolution. The structure of the antigen combining site in the complex is nearly identical to that of the complexed form of the parent mouse antibody, D1.3. In contrast, the combining sites of the unliganded mouse and humanized antilysozymes show moderate conformational differences. This disparity suggests that a conformational readjustment process linked to antigen binding reverses adverse conformations in the complementarity determining regions that had been introduced by engineering these segments next to human framework regions in the humanized antibody.     

抗血小板人源化抗体的研究进展

血小板在出血和血栓性疾病中发挥着重要作用.抗血小板人源化抗体在治疗特发性血小板减少性紫癜和防止血栓性疾病方面有极大的临床应用价值.本文就血小板在出血和血栓性疾病中的作用,人源化抗体的发展现状和抗血小板人源化抗体在出血性及血栓性疾病中的应用作一综述.     

Positron Emission Tomography Imaging of Endometrial Cancer Using Engineered Anti-EMP2 Antibody Fragments

Purpose

As imaging of the cell surface tetraspan protein epithelial membrane protein-2 (EMP2) expression in malignant tumors may provide important prognostic and predictive diagnostic information, the goal of this study is to determine if antibody fragments to EMP2 may be useful for imaging EMP2 positive tumors.

Procedures

The normal tissue distribution of EMP2 protein expression was evaluated by immunohistochemistry and found to be discretely expressed in both mouse and human tissues. To detect EMP2 in tumors, a recombinant human anti-EMP2 minibody (scFv-hinge-C_H3 dimer; 80 kDa) was designed to recognize a common epitope in mice and humans and characterized. In human tumor cell lines, the antibody binding induced EMP2 internalization and degradation, prompting the need for a residualizing imaging strategy. Following conjugation to DOTA (1,4,7,10-tetraazacyclododecane-N,N′,N′,N′″-tetraacetic acid), the minibody was radiolabeled with ⁶⁴Cu (t _1/2?=?12.7 h) and evaluated in mice as a positron emission tomography (PET) imaging agent for human EMP2-expressing endometrial tumor xenografts.

Results

The residualizing agent, ⁶⁴Cu-DOTA anti-EMP2 minibody, achieved high uptake in endometrial cancer xenografts overexpressing EMP2 (10.2?±?2.6, percent injected dose per gram (%ID/g) ± SD) with moderate uptake in wild-type HEC1A tumors (6.0?±?0.1). In both cases, precise tumor delineation was observed from the PET images. In contrast, low uptake was observed with anti-EMP2 minibodies in EMP2-negative tumors (1.9?±?0.5).

Conclusions

This new immune-PET agent may be useful for preclinical assessment of anti-EMP2 targeting in vivo. It may also have value for imaging of tumor localization and therapeutic response in patients with EMP2-positive malignancies.     

人源化CD25单克隆抗体对外周血T淋巴细胞活化和增殖的影响

本研究探讨人源化重组CD25单克隆抗体（rhCD25MAb）对外周血T淋巴细胞活化、增殖的影响。应用植物血凝素（PHA）刺激外周血单个核细胞，不加或同时加rhCD25MAb或环孢菌素A（CsA）进行体外培养，或先用PHA刺激T细胞活化后再加入rhCD25MAb继续进行培养。用MTT法检测淋巴细胞增殖率；流式细胞术检测T淋巴细胞表面抗原CD3、CD25的表达；ELISA方法检测细胞培养上清液中可溶性IL-2R（sIL-2R）水平。结果显示：rhCD25MAb和CsA均能有效抑制PHA活化的T细胞的增殖，且随浓度的升高而增强，总体比较，CsA对T细胞的增殖抑制作用更强。虽然CsA和rhCD25MAb均能降低细胞培养上清中的sIL-2R的水平及CD25^＋／CD3^＋的比例，但rhCD25MAb的作用明显强于CsA。rhCD25MAb无论是在T细胞活化前还是活化后均能抑制T细胞表达CD25抗原和分泌sIL-2R。结论：rhCD25MAb具有很强的免疫抑制作用，它能抑制T细胞活化及抑制活化的T细胞增殖，临床上它不仅可用于治疗急性移植物抗宿主病（aGVHD），还可用于预防aGVHD。     

CD137及其配体与肿瘤关系研究进展

CD137是肿瘤坏死因子受体(TNFR)家族成员之一,表达在活化T细胞、B细胞、NK1.1及活化的单核细胞表面上.活化细胞表面CD137与其配体结合后,介导的共刺激信号,是CD28/B7之外的另一重要的共刺激信号.CD137介导的协同刺激信号,可依赖或不依赖CD28途径发挥共刺激作用,调节T细胞、B细胞、单核细胞、NK1.1的活化、分化、增殖,提高免疫细胞的作用,阻止活化诱导的细胞的凋亡,在一定条件下具有抗肿瘤的作用和加速移植排斥反应.因此,CD137与其配体既参与机体免疫调节,又介导了免疫病理.CD137与其配体在不同的病人体内表达水平不一致,不仅影响机体的抗肿瘤作用,而且对肿瘤的发生、发展和预后具有重要意义.     

Mediastinal Imaging in Lung Cancer

Sixty-six patients with lung cancer underwent mediastinal stagingwith gallium scanning, CT scanning and mediastinal explorationat mediastinoscopy and/or thoracotomy. Histological findingsat time of mediastinal exploration were correlated with theresults of the non-invasive staging scans. Gallium scanninghad an accuracy of 78.8 per cent and CT scanning had an accuracyof 77.3 per cent. There was no evidence of increased test accuracyby performing both scans in the same individual. Either scanningtechnique may be utilised as a simple non-invasive mediastinalstaging procedure, and where negative it is appropriate to proceeddirectly to thoractomy.     

A Novel Investigational Fc-Modified Humanized Monoclonal Antibody,Motavizumab-YTE,Has an Extended Half-Life in Healthy Adults

The study objective was to evaluate the pharmacokinetics (PK), antidrug antibody (ADA), and safety of motavizumab-YTE (motavizumab with amino acid substitutions M252Y/S254T/T256E [YTE]), an Fc-modified anti-respiratory syncytial virus (RSV) monoclonal antibody. Healthy adults (n = 31) were randomized to receive a single intravenous (i.v.) dose of motavizumab-YTE or motavizumab (0.3, 3, 15, or 30 mg/kg) and followed for 240 days. Clearance of motavizumab-YTE was significantly lower (71% to 86%) and the half-life (t_1/2) was 2- to 4-fold longer than with motavizumab. However, similar peak concentrations and volume-of-distribution values, indicative of similar distribution properties, were seen at all dose levels. The sustained serum concentrations of motavizumab-YTE were fully functional, as shown by RSV neutralizing activity that persisted for 240 days with motavizumab-YTE versus 90 days postdose for motavizumab. Safety and incidence of ADA were comparable between groups. In this first study of an Fc-modified monoclonal antibody in humans, motavizumab-YTE was well tolerated and exhibited an extended half-life of up to 100 days. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00578682","term_id":"NCT00578682"}}NCT00578682.)     

MR Imaging in the Management of Patients with Breast Cancer

Magnetic resonance (MR) imaging has high sensitivity in detecting and determining the extent of breast cancer and the information provided by this modality has proven valuable in patient management. Investigations defining the strengths of MR imaging, technical advances, and greater standardization of protocols have led to its increased use in patients with breast cancer, both before and following treatment. This article reviews techniques and procedures used in the performance and interpretation of breast MR examinations. Applications of MR imaging in the management of patients with breast cancer are also summarized, including preoperative evaluation of extent of disease, postoperative assessment of residual disease, and the detection of recurrent carcinoma. The use of MR imaging to evaluate patient response to chemotherapy and to assess patients with axillary lymph node metastases with an unknown primary lesion will also be discussed.     

小乳腺癌的彩色多普勒超声诊断

本文报告经手术及病理证实直径≤２．０ｃｍ的乳腺肿物６１例，计７３个病灶的彩色多普勒（ＣＤＩ）超声检查结果。其中，恶性病变３９例，计４３个病灶；良性病变２２例，计３０个病灶。提出了我们的ＣＤＩ半定量分型标准（ＣＤＩ－ＨＱＡ）：Ⅰ型：病变区０～１处探及浅淡小点状血流信号，多单色、无彩色混叠现象，且血流信号主要出现于病灶周边部。Ⅱ型：病变区１～２处探及较亮点状，细条状血流信号，可有彩色混叠现象。血流信号以周边为主，偶见伸入病灶实质内。Ⅲ型：病变区３处以上探及明亮粗大点状和／或条状、树枝状血流信号，且病灶周边和实质内均易探及，并常有彩色混叠现象。我们将病灶血供属Ⅱ～Ⅲ型者，Ｖｍａｘ≥０．２０ｍ／ｓ和ＲＩ≥０．７０作为恶性肿瘤的阳性诊断指标；提出将其中二项以上指标呈阳性表现者作为小乳腺癌的诊断标准。结果本组诊断敏感性达９０．７％（３９／４３），特异性达９０％（２７／３０），准确性达９０．４％（６６／７３），优于彩色多普勒半定量、阻力指数或最高流速的单一指标分析法（Ｐ值＜０．０１），提高了彩超对≤２．０ｃｍ乳腺癌的诊断能力。初步结果表明，这种小乳腺癌彩超检查综合分析法，在临床应用中具有更客观准确、简便实用的优点。