Engineered humanized dimeric forms of IgG are more effective antibodies.

Caron, Philip; Laird, W; Co, Man Sung; Avdalovic, Nevenka M.; Queen, Cary; Scheinberg, David A.

doi:10.1084/jem.176.4.1191

Cited by 35 publications

(20 citation statements)

References 26 publications

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“…Although the relation of ADCC and the redistribution into lipid rafts has been poorly defined, high density of IgG1 bound on CD20 multimer or localized CD20 in lipid rafts may induce ADCC even by high-fucose IgG1. The hypothesis that clustering IgG1 could enhance ADCC is supported by the reports of dimerized antibodies having potent ADCC (42,43).…”

Section: Discussionsupporting

confidence: 58%

Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density

Niwa¹,

Sakurada²,

Kobayashi³

et al. 2005

Clinical Cancer Research

173

123

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Purpose: Recent studies have revealed that fucose removal from the oligosaccharides of human IgG1 antibodies results in a significant enhancement of antibody-dependent cellular cytotoxicity (ADCC) via improved IgG1 binding to Fc;RIIIa. In this report, we investigated the relationship between enhanced ADCC and antigen density on target cells using IgG1 antibodies with reduced fucose.Experimental Design: Using EL4 cell-derived transfectants with differential expression levels of exogenous human CC chemokine receptor 4 or human CD20 as target cells, ADCC of fucose variants of chimeric IgG1 antibodies specific for these antigens were measured. We further investigated IgG1 binding to natural killer (NK) cells and NK cell activation during ADCC induction to elucidate the mechanism by which low-fucose IgG1 induces ADCC upon target cells with low antigen expression.Results: Low-fucose IgG1s showed potent ADCC at low antigen densities at which their corresponding highfucose counterparts could not induce measurable ADCC. The quantitative analysis revealed that fucose depletion could reduce the antigen amount on target cells required for constant degrees of ADCC induction by 10-fold for CC chemokine receptor 4 and 3-fold for CD20. IgG1 binding to NK cells was increased by ligating IgG1 with clustered antigen, especially for low-fucose IgG1. Up-regulation of an activation marker, CD69, on NK cells, particularly the CD56 dim subset, in the presence of both the antibody and target cells was much greater for the low-fucose antibodies.Conclusions: Our data showed that fucose removal from IgG1 could reduce the antigen amount required for ADCC induction via efficient recruitment and activation of NK cells.

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Section: Discussionsupporting

confidence: 58%

Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density

Niwa¹,

Sakurada²,

Kobayashi³

et al. 2005

Clinical Cancer Research

173

123

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“…[8][9][10] Antibody polymerization, coupling with internalizable entities (eg, transferrin or urokinase), and other strategies have been explored to facilitate internalization. [11][12][13] Constraints for intracellular delivery depend on cell type and the nature of a target antigen. Among other cells, vascular endothelium is an important target.…”

Section: Introductionmentioning

confidence: 99%

Size-dependent intracellular immunotargeting of therapeutic cargoes into endothelial cells

Wiewrodt

Thomas

Cipelletti

et al. 2002

Blood

115

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IntroductionTargeted intracellular drug delivery needed for more effective and safe therapies requires both cell-specific recognition and subsequent internalization. Many internalizable determinants (eg, transferrin receptor) do not enable cell-specific recognition. [1][2][3] Immunotargeting permits more specific targeting, 4-7 but many antibodies (even some antibodies against internalizable antigens, eg, thrombomodulin [TM]) are poorly internalized. [8][9][10] Antibody polymerization, coupling with internalizable entities (eg, transferrin or urokinase), and other strategies have been explored to facilitate internalization. [11][12][13] Constraints for intracellular delivery depend on cell type and the nature of a target antigen. Among other cells, vascular endothelium is an important target. Stably and highly expressed endothelial antigens, such as platelet endothelial cell adhesion molecule 1 (PECAM-1) or CD31 (a glycoprotein involved in transmigration of leukocytes) [14][15][16][17][18] and TM (CD 141, a glycoprotein controlling enzymatic activities of thrombin), 19 may be used as target determinants, since their blood levels are several orders of magnitude lower than in endothelial cells. [20][21][22] In addition to the targeting function, anti-PECAM may suppress inflammation. [23][24][25] Recent studies showed that monoclonal antibodies directed against these determinants (ie, anti-PECAM and anti-TM) could be used for immunotargeting to endothelial cells in vitro and in vivo. [26][27][28][29] Although endothelial cells poorly internalize anti-PECAM, anti-PECAM conjugated with streptavidin (SA) is readily internalized. 28 Both anti-PECAM/SA and anti-TM/SA serve as a carrier to deliver active enzymes and genes to pulmonary endothelial cells in intact animals. [26][27][28][29][30][31][32] However, the carrier properties optimal for intracellular targeting to endothelium have not been established.Conceivably, carrier size is an important parameter for the intracellular uptake, yet this issue has not been systematically addressed in the literature. Available data show that optimal particle size threshold for intracellular uptake varies in different cell types. 7,12,[33][34][35][36] Although macrophages internalize large complexes of 1 m in diameter or larger, [37][38][39] little is known about how the size of complexes affects their uptake by other cell types. There For personal use only. on May 9, 2018. by guest www.bloodjournal.org From are no studies on effects of size on endothelial internalization via constitutive surface adhesion molecules.The goal of the present study was (1) to determine whether size controls uptake of anti-PECAM conjugates and to define the maximum size threshold for the uptake by endothelial cells and (2) to evaluate whether the size of immunoconjugates directed against endothelial antigens controls their targeting and effect in vivo. We generated diverse anti-PECAM conjugates ranging from 80-to 5000-nm diameter and found that the conjugates smaller than 350 nm were preferentially inte...

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“…For example, fast endosomal traffic and escape are critical for activity of immunotoxins (45). Conversely, targeting drugs to parasitophorous vacuoles or lysosomes is preferable for antiparasitic and certain types of enzyme replacement therapies (15,25,55), and nuclear delivery is necessary for gene therapies (7,19,40).…”

Section: C1346mentioning

confidence: 99%

“…In an attempt to control the extent and specificity of cytosolic delivery, liposome carriers have been designed that are destabilized after intemalization at acidic pH in endocytic compartments prior to release of a drug or fiision with cell membranes [43]. Third, antibodies and their derivatives with multivalent binding sites facilitate cellular entry of liposomes [44][45][46][47][48]. Fourth, a more recent approach to cytosol delivery has been to couple proteins and sub-micron particles with the TAT-peptide fi-om HIV virus, which in some instances can enter cells in an energy independent manner, although they may require endocytosis in other cases [49,50].…”

Section: A Brief Overview Of Vascular Drug Delivery Systemsmentioning

confidence: 99%

Targeting of Drugs to ICAM for Treatment of Acute Lung Injury

Muzykantov¹

2004

PsycEXTRA Dataset

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_ Public reporting burden for this coliection of information is estimated to average 1 tiour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining " the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing Uiis bunjen to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highv^ay, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Papenrork Reduction Project (0704-0188), Washington, DC 20503 AGENCY USE ONLY (Leave blank) REPORT DATE April 2004 REPORT TYPE AND DATES COVERED Annual (11 Mar 2003 -10 Mar 2004) TITLE AND SUBTITLE Targeting of Drugs to ICAM for Treatment of Acute Lung Injury AUTHOR(S)Vladimir Muzykantov, Ph.D. FUNDING NUMBERS DAMD17-02-1-0197 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)University of Pennsylvania Philadelphia, PA 19104-6205 E-Mail: muzykantOmail. med. upenn. edu PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSORING / MONITORING AGENCY REPORT NUMBER SUPPLEMENTARY NOTESOriginal contains color plates: ALL DTIC reproductions will be in black and white 12a. DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 12b. DISTRIBUTION CODE ABSTRACT (Maximum 200 Words)In the second year, we characterized intracellular traffic and final destination of anti-CAM conjugates in endothelial cells (EC) and found that CAM-mediated endocytosis initiates an unusually slow vesicular traffic that delivers conjugates to lysosomes several hours after internalization. Further, auxiliary drugs that regulate these processes can be utilized for prolongation of therapeutic duration of internalized conjugates. We characterized a series of in-house models of human ALI (injection of anti-TM/GOX and hyperoxia in mice), studied dynamics and role of EC cell adhesion molecules and leukocytes in these models and developed a new, clinically relevant and reliable model of ALI, based on combined treatment with anti-TM/GOX and hyperoxia. We synthesized anti-CAM/SOD conjugate with proper targeting size (~200 nm), enzymatic activity and affinity to EC and documented that it accumulates in the pulmonary vasculature after intravenous injection, thus satisfying main requirements for subsequent testing in animal models of ALI. In vitro and in vivo fibrinolysis studies have been employed in order to select the optimal candidate fibrinolytic (a novel tPA derivative, Tenektase) for targeting to endothelial CAM. Design and production of optimized affinity carriers for this purpose is in progress. SUBJECT TERMSEndothelium, immunotargeting, oxidant stress, thrombosis, ICAM-1 Vladimir Muzykantov, PI, DAMD 17-02-1-0197 "ICAM Targeting in Acute Lung Injury" Second Annual ...

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Engineered humanized dimeric forms of IgG are more effective antibodies.

Cited by 35 publications

References 26 publications

Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density

Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density

Size-dependent intracellular immunotargeting of therapeutic cargoes into endothelial cells

Targeting of Drugs to ICAM for Treatment of Acute Lung Injury

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