Impact of the high tyrosine fraction in complementarity determining regions: measured and predicted effects of radioiodination on IgG immunoreactivity

Nikula, Tuomo; Bocchia, Monica; Curcio, Michael; Sgouros, George; Ma, Yufei; Finn, Ronald D.; Scheinberg, David A.

doi:10.1016/0161-5890(95)00052-g

Cited by 75 publications

(60 citation statements)

References 19 publications

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“…This permits the appending of multiple copies of various moieties along the CNT axis. CNT, in effect, would accommodate amplification of chelate moieties without sacrificing immunoreactivity, relative to antibody-based constructs (12,13). For example, a 200-nm-long CNT in this study was determined to have 114 available DOTA chelates and 6 intact antibodies per construct molecule.…”

Section: Discussionmentioning

confidence: 99%

“…The latter 2 features of CNT could lead to enormous amplification of one particular function or the ability to multifunctionalize the construct (9)(10)(11). For example, when ligands or radionuclide atoms are directly attached to antibodies, only a limited number can be attached before there is a loss in the inherent targeting function of the antibody (12,13). Hence, CNT could be appropriate as delivery platforms for diagnostic or therapeutic agents where multiple copies of targeting, radionuclide, drug, or fluorescent agents could be attached.…”

mentioning

confidence: 99%

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Tumor Targeting with Antibody-Functionalized, Radiolabeled Carbon Nanotubes

McDevitt¹,

Chattopadhyay²,

Kappel³

et al. 2007

Journal of Nuclear Medicine

426

349

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Single-walled carbon nanotubes (CNT) are mechanically robust graphene cylinders with a high aspect ratio that are comprised of sp 2 -bonded carbon atoms and possessing highly regular structures with defined periodicity. CNT exhibit unique mechanochemical properties that can be exploited for the development of novel drug delivery platforms. We hypothesized that novel prototype nanostructures consisting of biologics, radionuclides, fluorochromes, and CNT could be synthesized and designed to target tumor cells. Methods: Tumor-targeting CNT constructs were synthesized from sidewall-functionalized, water-soluble CNT platforms by covalently attaching multiple copies of tumorspecific monoclonal antibodies, radiometal-ion chelates, and fluorescent probes. The constructs were characterized spectroscopically, chromatographically, and electrophoretically. The specific reactivity of these constructs was evaluated in vitro by flow cytometry and cell-based immunoreactivity assays and in vivo using biodistribution in a murine xenograft model of lymphoma. Results: A soluble, reactive CNT platform was used as the starting point to build multifunctional constructs with appended antibody, metal-ion chelate, and fluorescent chromophore moieties to effect specific targeting, to carry and deliver a radiometal-ion, and to report location, respectively. These nanoconstructs were found to be specifically reactive with the human cancer cells they were designed to target in vivo in a model of disseminated human lymphoma and in vitro by flow cytometry and cell-based immunoreactivity assays versus appropriate controls. Conclusion: The key achievement in these studies was the selective targeting of tumor in vitro and in vivo by the use of specific antibodies appended to a soluble, nanoscale CNT construct. The ability to specifically target tumor with prototype-radiolabeled or fluorescent-labeled, antibody-appended CNT constructs was encouraging and suggested further investigation of CNT as a novel delivery platform.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Tumor Targeting with Antibody-Functionalized, Radiolabeled Carbon Nanotubes

McDevitt¹,

Chattopadhyay²,

Kappel³

et al. 2007

Journal of Nuclear Medicine

426

349

View full text Add to dashboard Cite

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“…Preparation of ␥Ј-directed IgG Fab Fragments-For some experiments, fragment antibody binding (Fab) regions from the affinity-purified ␥Ј-peptide-directed IgG were generated by papain digestion (28), isolated with a Fab preparation kit (Pierce), assessed for purity by SDS-PAGE analysis, and then concentrated and dialyzed against HBS.…”

Section: Methodsmentioning

confidence: 99%

Histidine-rich Glycoprotein Binds Fibrin(ogen) with High Affinity and Competes with Thrombin for Binding to the γ′-Chain

Stafford

Leslie

et al. 2011

Journal of Biological Chemistry

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Histidine-rich glycoprotein (HRG) is an abundant protein that binds fibrinogen and other plasma proteins in a Zn2؉ -dependent fashion but whose function is unclear. HRG has antimicrobial activity, and its incorporation into fibrin clots facilitates bacterial entrapment and killing and promotes inflammation. Although these findings suggest that HRG contributes to innate immunity and inflammation, little is known about the HRGfibrin(ogen) interaction. By immunoassay, HRG-fibrinogen complexes were detected in Zn 2؉ -supplemented human plasma, a finding consistent with a high affinity interaction. Fibrinogen is the soluble precursor of fibrin, a critical component of blood clots that endows them with strength and elasticity. Fibrinogen is a glycoprotein composed of three pairs of polypeptide chains, termed A␣, B␤, and ␥, that are connected by disulfide bonds (1). Approximately 10 -15% of circulating fibrinogen has a variant ␥-chain termed the ␥Ј-chain, which results from differential processing of the ␥ A -chain mRNA transcript (2-4). The ␥Ј-chain is distinguished from the ␥ A -chain by the presence of an acidic 20-residue extension at its COOH terminus (2, 5).Thrombin catalyzes the conversion of fibrinogen to insoluble fibrin, and during this process some thrombin remains bound to the fibrin network (6). Exosites 1 and 2 are two regulatory domains that flank the active site of thrombin and mediate its binding to fibrin (7,8). Exosite 1 of thrombin interacts with the central E-domain of fibrin, whereas exosite 2 binds only to the COOH terminus of the ␥Ј-chain. Consequently, thrombin binds ␥ A /␥ A -fibrin in a univalent fashion with a K d value of 2-4 M. In contrast, both exosites are engaged when thrombin binds to ␥ A /␥Ј-fibrin, resulting in a higher affinity interaction (K d value of 0.08 -0.18 M) (5, 9). Fibrin-bound thrombin remains active, and the protease is protected from inhibition by fluid-phase inhibitors, such as antithrombin and heparin cofactor II (6). Because of its bivalent interaction with ␥ A /␥Ј-fibrin, thrombin bound to ␥ A /␥Ј-fibrin is more protected from inhibition by fluid-phase inhibitors than thrombin bound to ␥ A /␥ Afibrin (10).Like thrombin, histidine-rich glycoprotein (HRG) 3 binds to fibrinogen and is incorporated into fibrin clots (11). Although the plasma concentration of HRG ranges from 1.6 to 2 M, the concentration in platelet-rich thrombi may be higher because HRG is stored in the alpha granules of platelets and is released when platelets are activated (12, 13). A 75-kDa glycoprotein, HRG, is composed of two NH 2 -terminal cystatin-like domains, a central histidine-rich region (HRR) flanked by two prolinerich regions, and a COOH-terminal domain (14). In addition to fibrinogen, HRG also binds plasminogen, heparan sulfate, and divalent cations, such as Zn 2ϩ (12,15,16). Therefore, HRG is hypothesized to be an important accessory or adapter protein that brings different ligands together under specific conditions (14).HRG-deficient mice exhibit a shorter prothrombin time and accelerat...

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“…Sabe-se que a retenção de imunoreatividade integral de anticorpos monoclonais radiomarcados é condição fundamental para obter resultado satisfatório em radioimunoterapia. Pois o uso de imunoconjugados imunoincompetentes ou instáveis só contribuirá para a irradiação não-especifica do paciente sem contribuir para a irradiação específica do tumor [38,83,84]. Segundo Schaffland e colaboradores [38], Nikula e colaboradores [85], e Matzku e colaboradores [86], a diminuição de imunoreatividade observada em anticorpos monoclonais radiomarcados pode ser resultado de vários parâmetros químicos ou impurezas presente no iodo-131 bem como do grau de iodação do anticorpo (mono ou poli-iodado), sendo que esses fatores podem diferir significativamente para diferentes imunoglobulinas (IgGs) [38,85,86].…”

Section: Discussionunclassified

“…O grau de captação apresentado pelos órgãos está em consonância com os resultados obtidos em outros estudos realizados por outros pesquisadores em ensaios clínicos em humanos com anticorpo anti-CD20 marcado com iodo-131 e ítrio-90. A captação apresentada pelo sangue pode ser considerada como o reflexo de radioatividade circulante nos órgãos e tecidos [84,87,88]. A principal via de eliminação da atividade é renal, o que explica a captação alta demonstrada por esses órgãos.…”

Section: Discussionunclassified

"Estudo de marcação com Iodo-131 de anticorpo monoclonal anti-CD20 usado na terapia de linfoma não-Hodgkin"

Akanji¹

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Impact of the high tyrosine fraction in complementarity determining regions: measured and predicted effects of radioiodination on IgG immunoreactivity

Cited by 75 publications

References 19 publications

Tumor Targeting with Antibody-Functionalized, Radiolabeled Carbon Nanotubes

Tumor Targeting with Antibody-Functionalized, Radiolabeled Carbon Nanotubes

Histidine-rich Glycoprotein Binds Fibrin(ogen) with High Affinity and Competes with Thrombin for Binding to the γ′-Chain

"Estudo de marcação com Iodo-131 de anticorpo monoclonal anti-CD20 usado na terapia de linfoma não-Hodgkin"

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