Comparison of the monoclonal antibodies 17-1A and 323/A3: the influence of the affinity on tumour uptake and efficacy of radioimmunotherapy in human ovarian cancer xenografts

Kievit, Els; Pinedo, H.M.; Schlüper, Hennie M.M.; Haisma, Hidde J.; Boven, Epie

doi:10.1038/bjc.1996.81

Cited by 30 publications

(19 citation statements)

References 13 publications

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“…Immunoperoxidase staining with 323/A3 showed that EGP40 was homogeneously distributed in each of the ovarian cancer xenografts and was highly expressed on the membrane. Autoradiography of the high-affinity MAb 323/A3 in FMa, OVCAR-3 and Ov.Sh xenografts indicated that 323/A3 was mostly located near blood vessels, while the low-affinity anti-EGP40 MAb 17-1A showed a homogeneous distribution pattern (Kievit et al, 1996). The preferential binding of high-affinity MAbs to tumor cells near blood vessels can likely be overcome by increasing the protein dose of the MAb (Blumenthal et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

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Determination of tumor-related factors of influence on the uptake of the monoclonal antibody 323/A3 in experimental human ovarian cancer

et al. 1997

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The epithelial glycoprotein 40 (EGP40) is an important target in the clinic for radioimmunolocalization and monoclonal antibody (MAb)-mediated therapy of cancer. We determined which tumor-related factors (including antigen distribution and density, vascularization and perfusion) were involved in the uptake of the anti-EGP40 MAb 323/A3 in 4 different human ovarian cancer xenografts grown s.c. in nude mice. The reactivity pattern of 323/A3 in all xenografts in vitro was similar and showed a strong and homogeneous distribution of the EGP40 antigen. FMa xenografts, however, showed the highest uptake of 323/A3 in vivo, which was 5.5-, 6.2-and 10.0-fold higher than that in OVCAR-3, Ov.Pe and Ov.Sh xenografts, respectively. FMa xenografts contained 2.1-to 3.5-fold more antigen per gram protein when compared with the antigen content of the other xenografts. FMa and Ov.Sh xenografts demonstrated a better vascularization pattern, whereas Ov.Pe and OVCAR-3 xenografts were moderately to poorly vascularized. FMa xenografts were also better perfused, as was shown by a 1.6-to 1.8-fold higher uptake of the 99m Tc-labeled blood flow marker hexamethylpropyleneamine oxime (HMPAO). The tumor uptake of the non-specific MAb E48 was 2.2-to 11.2-fold lower when compared with that of 323/A3, but the sequence of uptake was similar (FMa G OVCAR-3 5 Ov.Pe G Ov.Sh), indicating the lowest extravasation of MAbs in Ov.Sh xenograft tissue. Since both the antigen content and the perfusion appeared to be important factors of influence on the tumor uptake of 323/A3, attempts were made to manipulate these determinants to improve the tumor uptake. Neither g-interferon nor 5-fluorouracil were able to increase EGP40 expression in human ovarian cancer cells in vitro. Treatment of tumor-bearing mice with the calcium-antagonist flunarizine did not result in an improved perfusion, although a slight increase in the initial tumor uptake of 323/A3 was observed in Ov.Sh-bearing mice. Our results illustrate the relative contribution of various tumorrelated factors that determine the usefulness of a MAb for imaging and therapy of cancer. Int.

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Section: Discussionmentioning

confidence: 99%

“…The MAbs 323/A3 and E48 were labeled with 125 I or 131 I (Amersham, 8s-Hertogenbosch, The Netherlands) with the use of iodogen (Kievit et al, 1996). More than 97% iodine was incorporated into the MAbs, as measured by TCA precipitation.…”

Section: Reagents Mabs and Iodinationmentioning

confidence: 99%

Determination of tumor-related factors of influence on the uptake of the monoclonal antibody 323/A3 in experimental human ovarian cancer

et al. 1997

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“…Similarly, in multiple subcutaneous tumor xenograft models, it was observed that a low affinity mAb was more homogenously distributed throughout the tumor than a mAb with a fivefold higher affinity. 21 While the range of affinities used in these studies was limited, or only compared a functional mAb to a nonspecific isotype matched control, the studies did demonstrate successfully that binding of antigen can limit penetration into a tumor.…”

Section: Experimental Analysis Of Affinity In the Binding Site Barriermentioning

confidence: 99%

Affinity and Avidity in Antibody-Based Tumor Targeting

Rudnick

Adams

2009

Cancer Biotherapy and Radiopharmaceuticals

202

170

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Many factors contribute to successful tumor targeting by antibodies. Besides properties of the tumor tissue and general antibody pharmacology, a relationship exists between an antibody and its antigen that can shape penetration, catabolism, specificity, and efficacy. The affinity and avidity of the binding interactions play critical roles in these dynamics. In this work, we review the principles that guide models predicting tumor penetration and cellular internalization while providing a critical overview of studies aimed at experimentally determining the specific role of affinity and avidity in these processes. One should gain the perspective that binding affinity can, in part, dictate the localization of antibodies in tumors, leading to high concentrations in the perivascular space or low concentrations diffused throughout the tumor. These patterns can be simply due to the diminution of available dose by binding antigen and are complicated by internalization and degradation stemming from slow rates of dissociation. As opposed to the trend of simply increasing affinity to increase efficacy, novel strategies that increase avidity and broaden specificity have made significant progress in tumor targeting.

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“…17-1A is a chimeric mAb is directed towards a ~39 kDa membrane-associated pancarcinoma glycoprotein (Edwards et al, 1986;Koprowski et al, 1979). It has been used in one animal study (Kievit et al, 1996). 323/A3 is a murine mAb that is directed to a ~39 kDa membrane-associated pancarcinoma glycoprotein (same as 17-1A) (Edwards et al, 1986;Koprowski et al, 1979).…”

Section: Targeting Constructsmentioning

confidence: 99%

“…It emits -radiation (364 keV) enabling scintigraphy and dosimetry. 131 I has been used in animal studies (Kievit et al, 1996;Turner et al, 1998) and in clinical studies (Buchsbaum et al, 1999;Buijs et al, 1998;Buist et al, 1993;Colcher et al, 1987;Crippa et al, 1995;Epenetos et al, 1987;Mahé et al, 1999;Molthoff et al, , 1997Muto et al, 1992;Stewart et al, 1989aStewart et al, , 1989bVan Zanten-Przybysz et al, 2000. 186 and 188 .…”

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confidence: 99%