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Monoclonal antibody conjugates of doxorubicin prepared with branched linkers:: A novel method for increasing the potency of doxorubicin immunoconjugates

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BIOCONJUGATE CHEMISTRY 1999年第2期10卷 279-288页

作者： King, HD Yurgaitis, D Willner, D Firestone, RA Yang, MB Lasch, SJ Hellström, KE Trail, PA Bristol Myers Squibb Co Pharmaceut Res Inst Wallingford CT 06492 USA Bristol Myers Squibb Co Pharmaceut Res Inst Princeton NJ 08543 USA Bristol Myers Squibb Pharmaceut Res Inst Seattle WA 98121 USA

Immunoconjugates of monoclonal antibody BR96 and Doxorubicin have been prepared using a novel series of branched hydrazone linkers. Since each Linker bound to the mAb carries two DOX molecules, the DOX/mAb molar ratios of these conjugates were approximately 16, twice that of those previously prepared with single-chain hydrazone linkers. The conjugates were stable at a physiological pH of 7, but released DOX rapidly at lysosomal pH 5. The branched series of BR96 conjugates demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a DOX (4-14-fold) and mAb (7-23-fold) basis. The results suggest that, by using the branched linker methodology, it is possible to significantly reduce the amount of mAb required to achieve antigen-specific cytotoxic activity. In this paper, the synthesis and in vitro biology of branched chain immunoconjugates are described.

关键词：抗体单克隆/代谢抗体单克隆/药代动力学细胞存活/药物作用多柔比星/药代动力学多柔比星/毒性腙类氢离子浓度水解作用免疫轭合物/化学免疫轭合物/药代动力学免疫轭合物/毒性免疫球蛋白G/代谢指示剂和试剂动力学肺肿瘤溶酶体/代谢肿瘤细胞培养的动物人类小鼠

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Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat

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ANNALS OF NEUROLOGY 2002年第4期51卷 433-441页

作者： Papadopoulos, CM Tsai, SY Alsbiei, T O'Brien, TE Schwab, ME Kartje, GL Loyola Univ Med Ctr Dept Cell Biol Neurobiol & Anat Maywood IL 60153 USA Loyola Univ Med Ctr Dept Neurol Maywood IL 60153 USA Loyola Univ Med Ctr Neurosci Program Maywood IL 60153 USA Hines Vet Affairs Hosp Neurol Serv Hines IL USA Hines Vet Affairs Hosp Res Serv Hines IL USA Swiss Fed Inst Technol Dept Biol Zurich Switzerland Univ Zurich Brain Res Inst Zurich Switzerland Loyola Univ Dept Math & Stat Ctr Stat Consulting Chicago IL 60611 USA Swiss Fed Inst Technol Dept Biol Zurich Switzerland Univ Zurich Brain Res Inst Zurich Switzerland

Stroke is a prevalent and devastating disorder, and no treatment is currently available to restore lost neuronal function after stroke occurs. One unique therapy that may improve functional recovery after stroke is blockade of the neurite inhibitory protein Nogo-A with the monoclonal antibody IN-1, through enhancement of neuroanatomical plasticity from uninjured areas of the central nervous system. In the present study, we combined IN-1 treatment with an ischemic lesion (permanent middle cerebral artery occlusion) to determine the effect of Nogo-A neutralization on cortical plasticity and functional recovery. We report here that, following ischemic stroke and treatment with IN-1, adult rats demonstrated functional recovery on a forelimb-reaching task and new cortico-efferent projections from the opposite, unlesioned hemisphere. These results support the efficacy of Nogo-A blockade as a treatment for ischemic stroke and implicate plasticity from the unlesioned hemisphere as a mechanism for recovery.

关键词：年龄因素抗体单克隆/药代动力学摄食行为梗死大脑中动脉/病理生理学梗死大脑中动脉/治疗髓磷脂蛋白质类/免疫学神经元可塑性大鼠 Long-Evans 功能恢复躯体感觉皮质/生理学动物男(雄)性大鼠

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Preparation, phototoxicity and biodistribution studies of anti-carcinoembryonic antigen monoclonal antibody-phthalocyanine conjugates

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PHOTOCHEMISTRY AND PHOTOBIOLOGY 1999年第6期70卷 930-936页

作者： Carcenac, M Larroque, C Langlois, R van Lier, JE Artus, JC Pèlegrin, A CRLC Val dAurelle Paul Lamarque Lab Cancerol Expt & Immunociblage Tumeurs Ctr Rech Cancerol F-34298 Montpellier 5 France INSERM U128 Montpellier France Univ Sherbrooke Fac Med Sherbrooke PQ Canada

Immunophototherapy of cancer combines the specificity of a monoclonal antibody (MAb) to an overexpressed tumor marker with the phototoxic properties of a conjugated dye. Aluminum tetrasulfophthalocyanine (AlPcS4) was covalently coupled to a 35A7 MAb directed against carcinoembryonic antigen (CEA) via a five-carbon spacer chain (A(1)) to yield conjugates with a molar ratio ranging from 5 to 16 mol of AlPcS4 per mel of 35A7 MAb. Conjugates were labeled with radioiodine for characterization. The immunoreactivity of the conjugates, determined in a direct binding assay on CEA coupled to sepharose, was net modified by the coupled AlPcS(4)A(1) molecules. In vivo, these conjugates were evaluated in nude mice bearing human colon carcinoma xenografts (T380), 35A7 MAb-(AlPcS(4)A(1))(5), 35A7 MAb-(AlPcS(4)A(1))(12) and 35A7 MAb-(AlPcS(4)A(1))(16) conjugates displayed a tumor uptake of 35 +/- 5.0%, 40 +/- 5.7% and 32 +/- 3.3% of the injected dose per gram of tumor tissue, respectively, corresponding to an uptake of 97%, 104% and 91% as compared to that of the unconjugated 35A7 MAb. In each experimental group, the tumor-to-normal tissue ratios obtained with the conjugates were almost identical to those obtained with unconjugated 35A7 MAb. Average values of 1.8, 7 and about 30 were obtained for blood, liver and muscle, respectively. Phototoxic efficacy of the 35A7 MAb-(AlPcS(4)A(1))(12) conjugate was demonstrated in vitro on the LoVo cell line giving a 91% growth inhibition for a 2.50 mu g/mL AlPcS4A(1), concentration. We conclude that these conjugates demonstrate clear in vivo tumor-seeking capacity and in vitro photocytotoxic properties. Such conjugates could thus be promising candidate drugs for clinical photodynamic therapy of cancers expressing CEA.

关键词：抗体单克隆/药代动力学癌胚抗原/免疫学结肠肿瘤/药物疗法结肠肿瘤/免疫学结肠肿瘤/代谢结肠肿瘤/病理学荧光染料免疫毒素类/药代动力学免疫毒素类/毒性吲哚类/药代动力学吲哚类/毒性小鼠裸肿瘤移植有机金属化合物/药代动力学有机金属化合物/毒性辐射增敏药/药代动力学辐射增敏药/毒性组织分布移植异种肿瘤细胞培养的动物人类小鼠

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Rapid assessment of glycoprotein IIb/IIIa blockade with the platelet function analyzer PFA-100 during percutaneous coronary intervention

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AMERICAN HEART JOURNAL 2001年第2期141卷 226-233页

作者： Madan, M Berkowitz, SD Christie, DJ Jennings, LK Smit, AC Sigmon, KN Glazer, S Tcheng, JE Duke Clin Res Inst Durham NC USA Dade Behring Inc Miami FL USA Univ Tennessee Memphis TN USA

Background The platelet function analyzer PFA-100 (Dade Behring, Miami, Fla) evaluates platelet function by determining the time to occlusion of an aperture in a membrane coated with collagen and adenosine diphosphate or epinephrine as whole brood flows under shear stress conditions. Platelet aggregation causes aperture occlusion, and results are reported as closure time [CT). Interindividual variability is observed in the level of platelet inhibition achieved with use of the current abciximab dosing regimen (0.25-mg/kg bolus + 10-mug/min infusion for 12 hours). The relationships between specific levels of platelet inhibition and clinical efficacy and safety have not been fully established. Methods and Results We prospectively studied platelet function in 27 patients receiving abciximab during percutaneous coronary intervention. This evaluation included determinations of platelet-rich plasma aggregometry, receptor occupancy studies (D3 assay), and CT measurements at baseline and 10 minutes, 4 hours, 12 hours, and 24 hours after the bolus. All patients received abciximab, aspirin, and heparin;patients undergoing coronary stent implantation received aspirin and ticlopidine after the procedure. CT results were reported within 10 minutes after initiation of testing. For 96% of patients, CT was 300 seconds (maximum CT) immediately after abciximab bolus and remained so throughout the infusion. At 24 hours we observed variable recovery From platelet inhibition and in 72% of patients CT returned to normal (less than or equal to 130 seconds). Conclusions Findings with the PFA-100 were similar to results observed with platelet aggregometry and receptor occupancy measurements. Most patients treated with abciximab exhibit normalized platelet function at 24 hours despite moderate levels of receptor occupancy, suggesting dissociation between occupancy and function.

关键词：抗体单克隆/药代动力学抗体单克隆/治疗应用抗凝药/药代动力学抗凝药/治疗应用阿司匹林/药代动力学阿司匹林/治疗应用冠状血管造影术冠心病/血液冠心病/放射摄影术冠心病/治疗药物疗法联合设备设计肝素/药代动力学肝素/治疗应用免疫球蛋白Fab片段/治疗应用监测生理学/仪器和设备血小板聚集/药物作用血小板聚集抑制剂/药代动力学血小板聚集抑制剂/治疗应用血小板糖蛋白GPⅡb-Ⅲa复合物/拮抗剂和抑制剂血小板糖蛋白GPⅡb-Ⅲa复合物/代谢前瞻性研究青少年成年人老年人人类中年人

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Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages:: Evidence that oxidation-specific epitopes mediate macrophage recognition

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第11期96卷 6353-6358页

作者： Chang, MK Bergmark, C Laurila, A Hörkkö, S Han, KH Friedman, P Dennis, EA Witztum, JL Univ Calif San Diego Dept Med 0682 La Jolla CA 92093 USA Univ Calif San Diego Dept Chem La Jolla CA 92093 USA

Apoptosis is recognized as important for normal cellular homeostasis in multicellular organisms. Although there have been great advances in our knowledge of the molecular events regulating apoptosis, much less is known about the receptors on phagocytes responsible for apoptotic cell recognition and phagocytosis or the ligands on apoptotic cells mediating such recognition. The observations that apoptotic cells are under increased oxidative stress and that oxidized low-density lipoprotein (OxLDL) competes with apoptotic cells for macrophage binding suggested the hypothesis that both OxLDL and apoptotic cells share oxidatively modified moieties on their surfaces that serve as ligands for macrophage recognition. To test this hypothesis, we used murine monoclonal autoantibodies that bind to oxidation-specific epitopes on OxLDL. in particular, antibodies EO6 and EO3 recognize oxidized phospholipids, including l-palmitoyl 2-(5-oxovaleroyl) phosphatidylcholine (POVPC), and antibodies EO12 and EO14 recognize malondialdehydelysine, as in malondialdehyde-LDL. Using FAGS analysis, we demonstrated that each of these EO antibodies bound to apoptotic cells but not to normal cells, whereas control IgM antibodies did not. Confocal microscopy demonstrated cell-surface expression of the oxidation-specific epitopes on apoptotic cells. Furthermore, each of these antibodies inhibited the phagocytosis of apoptotic cells by elicited peritoneal macrophages, as did OxLDL. In addition, an adduct of POVPC with BSA also effectively prevented phagocytosis. These data demonstrate that apoptotic cells express oxidation-specific epitopes-including oxidized phospholipids-on their cell surface, and that these serve as ligands for recognition and phagocytosis by elicited macrophages.

关键词：抗体单克隆/药代动力学抗体单克隆/药理学抗体特异性主动脉细胞凋亡地塞米松/药理学内皮血管/细胞学内皮血管/生理学表位/免疫学流式细胞术免疫球蛋白M/药理学脂蛋白类 LDL/免疫学巨噬细胞腹膜/细胞学巨噬细胞腹膜/生理学吞噬作用/生理学磷脂酰胆碱类/免疫学猪 T淋巴细胞/药物作用 T淋巴细胞/免疫学 T淋巴细胞/生理学动物小鼠

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Comparative pharmacodynamics of keliximab and clenoliximab in transgenic mice bearing human CD4

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期293卷 33-41页

作者： Sharma, A Davis, CB Tobia, LAP Kwok, DC Tucci, MG Gore, ER Herzyk, DJ Hart, TK SmithKline Beecham Pharmaceut Dept Drug Metab & Pharmacokinet King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Safety Assessment King Of Prussia PA 19406 USA

Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibodies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetics (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic mice bearing human CD4 molecules on their T cells after a single i.v. administration at three dose levels (5-125 mg/kg). The PK of keliximab and clenoliximab were similar, dose-dependent, and adequately described by a two-compartment model with saturable elimination from both compartments, The enumeration of circulating CD4(+) T cells and density of CD4 on their surface were determined as the PD effects. An indirect response model was proposed to characterize the PD effects. With the increase in mAb dose, the maximum intensity (R-max ) of PD effects was increased, and the time to reach R-max shifted to later times. At all three dose levels, keliximab caused a relatively rapid decline in the number of circulating CD4(+) T cells, which then recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg) did not produce a significant effect on CD4(+) T cell counts compared with the placebo group. At high doses, clenoliximab caused a significant decrease in the number of CD4(+) T cells. Keliximab appeared to be more potent and efficient in depleting CD4(+) T cells. Both mAbs produced similar down-modulation of CD4 at corresponding dose levels. The findings of this study are consistent with the results of a recent clinical trial that emphasize the importance of this transgenic mouse model for evaluating PK/PD to support clinical development of anti-human CD4 mAbs.

关键词：抗体单克隆/诊断应用抗体单克隆/药代动力学抗体单克隆/药理学抗原 CD4/遗传学抗原 CD4/代谢 CD4阳性T淋巴细胞/药物作用剂量效应关系药物流式细胞术淋巴细胞计数/药物作用小鼠转基因模型生物学动物人类男(雄)性小鼠

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Efficient clearance of poly(ethylene glycol)modified immunoenzyme with anti-PEG monoclonal antibody for prodrug cancer therapy

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BIOCONJUGATE CHEMISTRY 2000年第2期11卷 258-266页

作者： Cheng, TL Chen, BM Chern, JW Wu, MF Roffler, SR Acad Sinica Inst Biomed Sci Taipei Taiwan Natl Taiwan Univ Sch Pharm Taipei 10764 Taiwan Natl Taiwan Univ Coll Med Taipei 10018 Taiwan

The F(ab')(2) fragment of the anti-TAG-72 antibody, B72.3, was covalently linked to Escherichia coli-derived P-glucuronidase that was modified with methoxypoly(ethylene glycol). The conjugate (B72.3-beta G-PEG) localized to a peak concentration in LS174T xenografts within 48 h after injection, but enzyme activity persisted in plasma such that prodrug administration had to be delayed for at least 4 days to avoid systemic prodrug activation and associated toxicity. Conjugate levels in tumors decreased to 36% of peak levels at this time. Intravenous administration of AGP3, an IgM mAb against methoxypoly(ethylene glycol), accelerated clearance of conjugate from serum and increased the tumor/blood ratio of B72.3-beta G-PEG from 3.9 to 29.6 without significantly decreasing the accumulation of conjugate in tumors. Treatment of nude mice bearing established human colon adenocarcinoma xenografts with B72.3-beta G-PEG followed 48 h later with AGP3 and a glucuronide prodrug of p-hydroxyaniline mustard significantly (p less than or equal to 0.0005) delayed tumor growth with minimal toxicity compared to therapy with a control conjugate or conventional chemotherapy.

关键词：苯胺氮芥/类似物和衍生物苯胺氮芥/化学苯胺氮芥/治疗应用苯胺氮芥/毒性抗体单克隆/化学抗体单克隆/药代动力学抗体单克隆/治疗应用抗肿瘤药/化学抗肿瘤药/治疗应用抗肿瘤药/毒性细胞存活/药物作用疾病模型动物药物载体/化学药物载体/药代动力学大肠杆菌/酶学葡糖醛酸糖苷酶/化学葡糖醛酸糖苷酶/免疫学葡糖醛酸糖苷酶/药代动力学免疫酶技术/方法免疫球蛋白Fab片段/化学碘放射性同位素/诊断应用小鼠近交BALBC 小鼠裸肿瘤移植聚乙烯二醇类/化学聚乙烯二醇类/药代动力学药物前体/化学药物前体/药代动力学药物前体/治疗应用组织分布移植异种肿瘤细胞培养的动物人类小鼠

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Pharmacodynamic profile of short-term readministration of abciximab in healthy subjects

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AMERICAN HEART JOURNAL 2002年第1期143卷 87-94页

作者： Freedman, J Mascelli, MA Pezzullo, JC Barnathan, ES Frederick, B Jordan, RE Albernethy, DR Centocor Inc Malvern PA 19355 USA Georgetown Univ Sch Med Washington DC USA Natl Inst Aging Baltimore MD USA

Objective The purpose of the study was to establish a rebolus regimen for abciximab that restores pharmacologic glycoprotein (GP) IIb/IIIa receptor blockade within a short time frame (up to 48 hours) after completion of an initial treatment. Methods and Results The study was a single-center, nonrandomized, open-label dose escalation trial in healthy volunteers (n = 30). Each subject received a 0.25 mg/kg bolus and a 0.125 mug/kg per minute infusion of abciximab, followed by incremental bolus doses of the agent at 15-minute intervals up to 48 hours (10 per group) after completion of the infusion, (maximal cumulative rebolus dose of 0.25 mg/kg). Pharmacodynamic measurements (GP IIb/IIIa receptor blockade, turbidimetric and whole blood platelet aggregation with use of a rapid platelet function assay [RPFA]) were obtained at periodic intervals during and after administration of the abciximab bolus and infusion. At the time of the first rebolus, pharmacodynamic measurements were attained immediately before administration of each rebolus and 15 minutes after the last rebolus dose. In subjects who received reboluses 12 hours after infusion, a cumulative dose of 0.05 mg/kg restored >80% blockade of GP IIb/IIIa receptors and >80% inhibition of turbidimetric (5 and 20 mumol/L adenosine diphosphate) and RPFA aggregation in 10 of 10 subjects. At 24 hours after treatment, a cumulative abciximab bolus dose of 0.1 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. At 48 hours after treatment, a cumulative bolus dose of 0.15 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. Conclusions A fraction of the bolus of abciximab restored pharmacologic (>80%) GP IIb/IIIa receptor blockade when readministered at various postinfusion time points. These observations suggest that in the setting where acute readministration of abciximab is required less than a full bolus dose of the agent is warranted.

关键词：抗体单克隆/投药和剂量抗体单克隆/药代动力学用药计划表免疫球蛋白Fab片段/投药和剂量血小板聚集/药物作用血小板糖蛋白GPⅡb-Ⅲa复合物/拮抗剂和抑制剂时间因素成年人老年人人类男(雄)性中年人

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Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期291卷 1060-1067页

作者： Zia-Amirhosseini, P Minthorn, E Benincosa, LJ Hart, TK Hottenstein, CS Tobia, LAP Davis, CB SmithKline Beecham Dept Drug Metab & Pharmacokinet King Of Prussia PA USA SmithKline Beecham Dept Safety Assessment King Of Prussia PA USA

The pharmacokinetics (PK) of SB-240563 have been investigated after i.v. and s.c. administration to cynomolgus monkeys. Approximately linear PK was observed following i.v. administration over a 6000-fold dose range (0.05-300 mg/kg). After i.v. dosing, SB-240563 concentration declined in a biexponential manner with a mean terminal half-life of 13 +/- 2 days. The plasma clearance and volume of distribution at steady state were similar to 0.2 ml/h/kg and 70 ml/kg, respectively. Following s.c. administration, SB-240563 was completely absorbed into the systemic circulation. Because interleukin-5 is known to stimulate production, activation, and maturation of eosinophils, eosinophil counts were measured to assess pharmacologic activity of SB-240563. The maximal response (81-96% decrease in eosinophil count relative to baseline) following a single s.c. administration occurred at 3 weeks postdosing. Suppression of eosinophil count also was observed following multiple monthly administrations of SB-240563 to monkeys. The pharmacokinetic/pharmacodynamic relationship was generally well described with an indirect pharmacologic response model with an estimated IC50 value of 1.43 mu g/ml. The combination of a low IC50 value for reduction of circulating eosinophils and a long terminal half-life suggests the possibility of an infrequent dosing regimen for SB-240563 for treatment of diseases associated with increased eosinophil function such as asthma.

关键词：算法抗体单克隆/药代动力学抗体单克隆/药理学抗体特异性曲线下面积生物利用度 CHO细胞化学发光测定法仓鼠亚科交叉反应嗜酸细胞/药物作用半衰期注射静脉内注射皮下白细胞介素5/免疫学成束猴动物人类

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Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkeys

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期292卷 810-816页

作者： Benincosa, LJ Chow, FS Tobia, LP Kwok, DC Davis, CB Jusko, WJ SmithKline Beecham Pharmaceut Drug Metab & Pharmacokinet King Of Prussia PA 19406 USA SUNY Buffalo Sch Pharm Dept Pharmaceut Buffalo NY 14260 USA

The pharmacokinetics and pharmacodynamics (PK/PD) of a humanized anti-Factor IX IgG1 monoclonal antibody (SB 249417, FIX mAb) were studied in Cynomolgus monkeys. Single i.v. bolus doses of 1, 3, or 10 mg/kg of FIX mAb were administered. The total FIX mAb concentration, activated partial thromboplastin time (aPTT), and Factor IX activity were monitored for up to 4 weeks after dosing. In the monkey, FIX mAb had a plasma clearance of 0.6 ml/h/kg and a steady-state volume of distribution of approximately 70 ml/kg. The elimination phase half-life (3.8 days) was considerably less than other humanized IgG1 mAbs in the monkey, for which there is no binding to endogenous antigen. The suppression of Factor IX activity and the prolongation of aPTT were rapid and dose dependent. The time for aPTT values to return to basal levels (25-170 h) increased with increasing dose. A mechanism-based PK/PD model consistent with the stoichiometry of binding (2:1) was developed to describe the Factor IX activity and aPTT response time course. The model incorporated Factor IX synthesis and degradation rates that were interrupted by the sequestration of Factor IX by the antibody. aPTT values were related to free Factor IX activity. This model was able to describe the PD profiles from the three dose levels simultaneously. The estimated Factor IX half-life was 11 h and the third-order association rate constant was 3.96 x 10(3) mu M-2 h(-1). The PK/PD modeling was useful in summarizing the major determinants (endogenous and antibody-ligand binding) controlling FIX mAb-related effects.

关键词：抗体单克隆/免疫学抗体单克隆/药代动力学抗体单克隆/药理学剂量效应关系药物因子Ⅸ/免疫学因子Ⅸ/代谢免疫球蛋白G/代谢配体成束猴部分促凝血酶原时间蛋白质结合重组蛋白质类时间因素动物人类男(雄)性

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