TARGETING OF LIVER METASTASES WITH IgG, F(ab')2 and Fab' ANTI-CEA ANTIBODIES LABELED WITH 99mTc - THE ROLE OF METABOLISM AND KINETICS

Bchr, Th.; Becker, W.-M.; Goldenberg, D. M.; Wolf, F.

doi:10.1097/00002371-199408000-00029

Cited by 10 publications

(32 citation statements)

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“…The antigen was covalently immobilized on a CM5 sensor chip through thiol ligation. To analyze the binding of soluble molecules, pFabЈ, pF(abЈ) 2 , rFabЈ, rF(abЈ) 2 and rcF(abЈ) 2 antibody fragments were injected at a concentration of 50 g/ml in HBS-EP buffer [0.01 M HEPES (pH 7.4), 0.15 M NaCl, 3 mM EDTA, 0.005% surfactant P20]. Sixty microliters of each sample were injected at a flow rate of 20 l/min, and sensor chips were regenerated using 10 l of 100 mM HCl.…”

Section: Affinity Of Cea Binding By Antibody Fragmentsmentioning

confidence: 99%

“…in the tail vein with 5 g of 125 I-labeled recombinant rFabЈ or rF(abЈ) 2 together with 5 g of 131 I-labeled nonrecombinant pF(abЈ) 2 (2.5 ϫ 10 6 cpm). Then, at selected time intervals, 6 mice were killed and dissected; radioactivity resulting in 125 I and 131 I emissions was measured for each organ and tissue.…”

Section: Biodistributionmentioning

confidence: 99%

“…The advantage of antibody fragments over intact antibodies is their smaller size, which correlates with their increased ability to penetrate the solid tumor mass rapidly and evenly. 2 The lack of Fc domains also makes antibody fragments intrinsically less immunogenic since a large percentage of the HAMA response, which can severely limit the efficacy of antibody therapy, is directed against the Fc region. 3 However, since antibody fragments are unable to trigger the effector functions of whole antibodies, they must be coupled to effector molecules such as radionuclides to kill tumor cells.…”

mentioning

confidence: 99%

“…Preparation of FabЈ or F(abЈ) 2 fragments by limited proteolysis and mild reduction of purified MAbs remains time-consuming and requires high amounts of the parental MAbs due to the low yield of the final product. Alternatively, genes coding for antibody fragments can be cloned and expressed in various ways to give new versions of antibodies that possess reduced immunogenicity, improved affinity, altered size, increased avidity and novel effector functions.…”

mentioning

confidence: 99%

“…5 This antibody fragment was further engineered by 1 cysteine/serine replacement in the hinge region and produced in Escherichia coli as a FabЈ or as the naturally occurring F(abЈ) 2 molecule. The FabЈ molecule was also dimerized into F(abЈ) 2 by chemical cross-linking. These molecules were purified and evaluated in vitro for binding to CEA-expressing cells using flow cytometry and by surface plasmon resonance.…”

mentioning

confidence: 99%

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Pharmacokinetic and tumor‐seeking properties of recombinant and nonrecombinant anti‐carcinoembryonic antigen antibody fragments

Groulet

Dorvillius²,

Pèlegrin³

et al. 2002

Intl Journal of Cancer

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Production of recombinant antibody fragments in bacterial expression systems results in intentional or fortuitous differences compared to the original products prepared by hybridoma technology. These differences may have significant effects not only on antigen-binding properties but also on pharmacokinetic and tumor-seeking properties. Our major goal was to investigate some of these possible differences. We produced in Escherichia coli an rFab fragment containing only 1 cysteine residue in the hinge region; the fragment was derived from a mouse MAb (F6) specific for CEA. The rFab had a slightly lower m.w. and a higher isoelectric point relative to the corresponding nonrecombinant fragment (pFab ). This was explained by the absence of N-glycosylation on the V domain of rFab . V glycosylation had no significant effect on antibody-binding affinity and kinetics. However, rFab was eliminated from the circulation much faster than pFab , and the maximal dose accumulated in the tumor was reduced relative to pFab . Thus, glycosylation appears to modify the targeting efficiency of antibody fragments. rF(ab ) 2 fragments were obtained either spontaneously from the culture supernatant of E. coli or by chemical cross-linking [rcF(ab ) 2 ]. We observed improved tumor targeting with rcF(ab ) 2 compared to rF(ab ) 2 , which could be explained by the greater stability of the thioether compared to the disulfide linkage. These results demonstrate that a single cysteine residue in the hinge region of rFab is particularly well suited to prepare stable, chemically coupled, bivalent or bispecific antibodies, avoiding intrahinge disulfide bonding and thus achieving higher production yields.

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Section: Affinity Of Cea Binding By Antibody Fragmentsmentioning

confidence: 99%

Section: Biodistributionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetic and tumor‐seeking properties of recombinant and nonrecombinant anti‐carcinoembryonic antigen antibody fragments

Groulet

Dorvillius²,

Pèlegrin³

et al. 2002

Intl Journal of Cancer

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Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism

et al. 2011

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A novel human monoclonal antibody specific to the A33 glycoprotein recognizes colorectal cancer and inhibits metastasis

Murer

Plüss

Neri

2020

mAbs

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Colorectal cancer represents the second most common cause of cancer-related death. The human A33 transmembrane glycoprotein is a validated tumor-associated antigen, expressed in 95% of primary and metastatic colorectal cancers. Using phage display technology, we generated a human monoclonal antibody (termed A2) specific to human A33 and we compared its epitope and performance to those of previously described clinical-stage anti-human A33 antibodies. All antibodies recognized a similar immunodominant epitope, located in the V-domain of A33, as revealed by SPOT analysis. The A2 antibody homogenously stained samples of poorly, moderately, and well differentiated colon adenocarcinomas. All antibodies also exhibited an intense staining of healthy human colon sections. The A2 antibody, reformatted in murine IgG2a format, preferentially localized to A33-transfected CT26 murine colon adenocarcinomas in immunocompetent mice with a homogenous distribution within the tumor mass, while other antibodies exhibited a patchy uptake in neoplastic lesions. A2 efficiently induced killing of A33-expressing cells through antibody-dependent cellmediated cytotoxicity in vitro and was able to inhibit the growth of A33-positive murine CT26 and C51 lung metastases in vivo. Anti-A33 antibodies may thus represent useful vehicles for the selective delivery of bioactive payloads to colorectal cancer, or may be used in IgG format in a setting of minimal residual disease.

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TARGETING OF LIVER METASTASES WITH IgG, F(ab')2 and Fab' ANTI-CEA ANTIBODIES LABELED WITH 99mTc - THE ROLE OF METABOLISM AND KINETICS

Cited by 10 publications

References 0 publications

Pharmacokinetic and tumor‐seeking properties of recombinant and nonrecombinant anti‐carcinoembryonic antigen antibody fragments

Pharmacokinetic and tumor‐seeking properties of recombinant and nonrecombinant anti‐carcinoembryonic antigen antibody fragments

Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism

A novel human monoclonal antibody specific to the A33 glycoprotein recognizes colorectal cancer and inhibits metastasis

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