Antibody‐antigen complex formation following injection of OC125 monoclonal antibody in patients with ovarian cancer

Haisma, Hidde J.; Battaile, Anne; Stradtman, Earl W.; Knapp, Robert C.; Zurawski, Vincent R.

doi:10.1002/ijc.2910400608

Cited by 20 publications

(10 citation statements)

References 13 publications

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“…However, Koji et al [7] and Ishii et al [8] reported that anti-AFP antibodies were deliv ered to hepatoma cells in spite of the presence of enough serum AFP to neutralize them. Similar results were reported with systems using anti-CEA MoAb [4] and other MoAbs [3,9], indicating that circulating antigen did not always interfere with tumor targeting. These results suggest that even circulating an tigens such as AFP or CEA can be suitable tar get candidates for tumor targeting when the selection of MoAbs against them is well op timized as targeting carriers.…”

Section: Introductionsupporting

confidence: 75%

Selective Antitumor Effect of Thioether-Linked Immunotoxins Composed of Gelonin and Monoclonal Antibody to Alpha-Fetoprotein or Its F(ab<sup>/</sup>)Fragment

et al. 1994

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Two thioether-linked conjugates composed of monoclonal antibody (MoAb) to α-fetoprotein (AFP), 80G or its F(ab′)2 fragment, and a type 1 ribosome-inactivating protein (RIP), gelonin, were prepared as potent immunotoxins [80G-CS-GL(IT) and F(ab′)2-CS-GL(IT)]. Each conjugate contained one gelonin per 80G or its F(ab′)2 fragment. The binding activity of these conjugates was as high as that of intact 80G or F(ab′)2· The in vitro cytotoxic effect of F(ab′)2-CS-GL(IT) on AFP-producing HuH-7 cells was approximately 100-fold more potent than that of 80G-CS-GL(IT). Also, F(ab′)2-CS-GL(IT) showed slight cytotoxicity against non-AFP-pro-ducing HuH-13 cells, while 80G-CS-GL(IT) did not. On the other hand, both conjugates had similar selective antitumor activity against HuH-7N cells in nude mice, possibly due to their similar distribution in the tumor. The results suggest that our MoAb 80G is a suitable carrier for delivering type 1 RIP such as gelonin into AFP-producing hepatoma cells and that its F(ab′)2 fragmentation does not enhance targeting efficiency.

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Section: Introductionsupporting

confidence: 75%

Selective Antitumor Effect of Thioether-Linked Immunotoxins Composed of Gelonin and Monoclonal Antibody to Alpha-Fetoprotein or Its F(ab<sup>/</sup>)Fragment

et al. 1994

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“…Of importance, when the concentration of 3A5 was increased while that of the antigen was held constant, the proportion of IC was low relative to total 3A5. The in vitro kinetics of IC formation was rapid, in line with that reported by Haisma et al (1987). IC formation between 3A5 and circulating CA125 was consistently detected in vivo in tumor-bearing mice only at low concentrations of the antibody relative to the antigen, which was determined by ELISA.…”

Section: Discussionsupporting

confidence: 87%

“…In some cases, the antigen is shed from the cell surface into the circulation where the antibody may form ICs with the circulating antigen, potentially affecting therapeutic efficacy by preventing it from reaching the tumor and/or altering the antibody kinetics of distribution and clearance (Bruno et al, 2005). A number of ovarian cancer preclinical and clinical studies have addressed the potential risks of shed antigen (Hagan et al, 1985;Haisma et al, 1987;Pimm et al, 1989;Kobayashi et al, 1993;Pimm, 1995;Sakahara et al, 1996;Davies et al, 1997;McQuarrie et al, 1997;Prinssen et al, 1998;Maeda et al, 2004). In patients with ovarian cancer, IC formation was detected upon delivery of an anti-CA125 antibody.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Immune Complex Formation on the Distribution of a Novel Antibody to the Ovarian Tumor Antigen CA125

Pastuskovas¹,

Mallet²,

Clark³

et al. 2010

Drug Metab Dispos

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ABSTRACT:3A5 is a novel antibody that binds repeated epitopes within CA125, an ovarian tumor antigen that is shed into the circulation. Binding to shed antigen may limit the effectiveness of therapeutic antibodies because of unproductive immune complex (IC) formation and/or altered antibody distribution. To evaluate this possibility, we characterized the impact of shed CA125 on the in vivo distribution of 3A5. In vitro, 3A5 and CA125 were found to form ICs in a concentration-dependent manner. This phenomenon was then evaluated in vivo using quantitative whole-body autoradiography to assess the tissue distribution of 125 I-3A5 in an orthotopic OVCAR-3 tumor mouse model at different stages of tumor burden. Low doses of 3A5 (75 g/kg) and pathophysiological levels of shed CA125 led to the formation of ICs in vivo that were rapidly distributed to the liver. Under these conditions, increased clearance of 3A5 from normal tissues was observed in mice bearing CA125-expressing tumors. Of importance, despite IC formation, 3A5 uptake by tumors was sustained over time. At a therapeutically relevant dose of 3A5 (3.5 mg/kg), IC formation was undetectable and distribution to normal tissues followed that of blood. In contrast, increased levels of radioactivity were observed in the tumors. These data demonstrate that CA125 and 3A5 do form ICs in vivo and that the liver is involved in their uptake. However, at therapeutic doses of 3A5 and clinically relevant CA125 levels, IC formation consumes only a minor fraction of 3A5, and tumor targeting seems to be unaffected.

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“…Numerous investigators have suggested that binding to circulating antigen will interfere with the ability of an antibody to target the tumor. In fact, studies have shown that antibodies that bind to shed CA 125 are quickly tied up in immune complexes following intravenous injection and are subsequently cleared from circulation [20][21][22][23] .…”

mentioning

confidence: 99%

Characterization of Antibodies to CA 125 that Bind Preferentially to the Cell-Associated Form of the Antigen

et al. 2006

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Objective: Antibodies to CA 125 have been used to predict relapse of ovarian cancer, but have performed poorly as therapeutic agents. One rationale for this is antibody binding to circulating shed antigen. Our aim in this study was to develop antibodies to human CA 125 that have enhanced selectivity for the cell-associated form of the antigen. Methods: Monoclonal antibodies were raised to a recombinant fragment of CA 125 that included sequence proximal to the putative membrane attachment site. Antibodies were characterized in terms of their binding site, affinity and selectivity for cell-associated CA 125. Results: In assays using patient-derived CA 125, a subset of high-affinity (K_D <5 nM) monoclonal antibodies demonstrated a 10- to greater than 200-fold increase in selectivity for cell-associated CA 125 when compared with controls. Based on mapping of the various monoclonal antibodies obtained, it was determined that shedding of CA 125 most likely occurs in the most C-terminal repeat domain. Conclusion: Results from competition analysis using patient-derived shed antigen predict that the antibodies described in this study may have significantly enhanced tumor-targeting properties when compared with existing antibodies to CA 125 in a tumor environment having high concentrations (>10,000 CA 125 units) of shed CA 125.

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Antibody‐antigen complex formation following injection of OC125 monoclonal antibody in patients with ovarian cancer

Cited by 20 publications

References 13 publications

Selective Antitumor Effect of Thioether-Linked Immunotoxins Composed of Gelonin and Monoclonal Antibody to Alpha-Fetoprotein or Its F(ab<sup>/</sup>)Fragment

Selective Antitumor Effect of Thioether-Linked Immunotoxins Composed of Gelonin and Monoclonal Antibody to Alpha-Fetoprotein or Its F(ab<sup>/</sup>)Fragment

Effect of Immune Complex Formation on the Distribution of a Novel Antibody to the Ovarian Tumor Antigen CA125

Characterization of Antibodies to CA 125 that Bind Preferentially to the Cell-Associated Form of the Antigen

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