Monoclonal antibody to an intracellular antigen images human melanoma transplants in nu/nu mice.

Welt, Sydney; Mattes, M. Jules; Grando, Robert; Thomson, Timothy M.; Leonard, R W; Zanzonico, Pat; Bigler, Rodney E.; Yeh, Samuel D. J.; Oettgen, Herbert F.; Old, Lloyd J.

doi:10.1073/pnas.84.12.4200

Cited by 35 publications

(19 citation statements)

References 9 publications

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“…As much as 70% of the total radioactivity in the animal was localized to the tumours after 2 weeks. This represents up to 15% of the ini tially injected dose, which is higher, to our knowledge, than has been reported for any other antigen-antibody system [2,21,22], PLAP-antiPLAP monoclonal antibodies, ex pressed in certain carcinoma cells, offer the potential of being valuable targets for radioimmunolocalization and radioimmuno therapy.…”

Section: Discussionmentioning

confidence: 82%

Tumour Radioimmunolocalization in Nude Mice by Use of Antiplacental Alkaline Phosphatase Monoclonal Antibodies

Stigbrand

Hietala²,

Johansson³

et al. 1989

Tumor Biol

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Three monoclonal antibodies and their Fab and Fab_2′ fragments with specificity against human placental alkaline phosphatase (PLAP) were evaluated for tumour immunolocalization of human PLAP-producing Hela Hep 2 tumours in nude mice. The antibodies and their fragments were labelled with ¹²⁵I and injected intraperitoneally in mice with developing Hep 2 tumours. The animals were followed individually for 14 days with repetitive computerized gamma-camera recordings, which enable quantitation of several crucial parameters, i.e. the time-dependent antibody uptake in the tumours, decrease in background activity and tumour/background ratio. Excellent radioimmunolocalization was obtained with both the intact PLAP-specific immunoglobulins and their fragments but not with the nonspecific antibodies. No background subtraction had to be used. As much as 15 % of the initially injected dose could be visualized in the tumours and for the uncleaved mab up to 80% of the radioactivity in the animals was retained in the tumours after 14 days, a considerably longer observation time than usually reported in such tumour xenograft models. The Fab and Fab_2′ fragments were found to be excreted fast with less than 5 % of the injected dose remaining in the animals after 48 h, but still with positive specific localization to the tumours after an initial high uptake in the kidneys. The results are encouraging and indicate significant potentials of the PLAP-antiPLAP mab system for immunolocalization studies in patients.

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Section: Discussionmentioning

confidence: 82%

Tumour Radioimmunolocalization in Nude Mice by Use of Antiplacental Alkaline Phosphatase Monoclonal Antibodies

Stigbrand

Hietala²,

Johansson³

et al. 1989

Tumor Biol

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“…Alternatively, melanosomal components, which are normally transported outside the melanocyte during maturation, could accumulate in the extracellular space around tumor cells, or local tissue necrosis could lead to release and deposition of intracellular products . In support of the accessibility of gp75, radiolabeled TA99 mAb specifically localizes to human melanoma xenografts in nu/nu mice (20), indicating the availability of the antigen to antibody within tumor sites.…”

Section: Resultsmentioning

confidence: 99%

The melanoma antigen gp75 is the human homologue of the mouse b (brown) locus gene product.

Setaluri

Bouchard

Houghton

1990

The Journal of Experimental Medicine

185

123

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The gp75 antigen is an abundant intracellular glycoprotein expressed in melanosomes of human pigmented melanocytes and melanomas. IgG antibodies in sera of a patient with metastatic melanoma have been shown to immunoprecipitate gp75, suggesting that immunological tolerance against gp75 can be broken. The mouse mAb TA99, which specifically recognizes gp75, was used to isolate and purify the antigen. Amino acid sequences of three internal peptides were determined from the purified gp75 polypeptide. cDNA clones were isolated by screening with oligonucleotides based on these peptide sequences. The gp75 peptides and cDNA had approximately 90% identity with, respectively, the derived amino acid and nucleotide sequences of a mouse gene that maps to the b (brown) locus. The brown locus determines coat color in the mouse, suggesting that gp75 regulates or influences the type of melanin synthesized.

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“…We hypothesized that melanin in melanoma tumors could be targeted by a melanin-binding Ab as a result of extracellular release from dead cells or by virtue of greater permeability of dying cells. Malignant tumors contain abnormally permeable degenerating cells, which make feasible targeting of mAbs to intracellular antigens (39,40). This approach is currently used for detection of prostate cancer, where the intracellular epitope of a prostate-specific membrane antigen is targeted with 111 In-labeled 7E11 mAb (ProstaScint; Cytogen, Princeton, NJ) (41).…”

Section: Discussionmentioning

confidence: 99%

Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin

Dadachova

Nosanchuk

Shi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Melanoma is a cancer with a rising incidence, and metastatic disease is almost always lethal. We investigated the feasibility of targeting melanin, an intracellular melanocyte pigment, to deliver cytotoxic radiation to human melanoma cells in vivo by using a melanin-binding mAb (6D2). Nude mice bearing MNT1 pigmented human melanoma tumors were treated with mAb 6D2 labeled with 1.5 mCi (1 Ci ‫؍‬ 37 GBq) of the ␤-emitter 188-Rhenium ( 188 Re) and manifested inhibition of tumor growth and prolonged survival. mAb 6D2 bound tumor melanin and demonstrated no crossreactivity with normal melanized tissues in black mice. The mechanism of melanin targeting involved Ab binding to extracellular melanin released during tumor cell turnover or to dying cells with permeable membranes. In this approach, the cytotoxic radiation emanating from labeled Ab bound to melanin is presumably delivered by ''crossfire'' effect to the adjacent viable tumor cells. Our results establish the feasibility of targeting melanin released from dead melanoma cells in tumors with radiolabeled Abs to achieve a therapeutic effect. In contrast to conventional tumor antigens, melanin is insoluble, resistant to degradation, and can be expected to accumulate in targeted tissues, suggesting that the efficacy of therapy could increase with each subsequent treatment cycle.

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Monoclonal antibody to an intracellular antigen images human melanoma transplants in nu/nu mice.

Cited by 35 publications

References 9 publications

Tumour Radioimmunolocalization in Nude Mice by Use of Antiplacental Alkaline Phosphatase Monoclonal Antibodies

Tumour Radioimmunolocalization in Nude Mice by Use of Antiplacental Alkaline Phosphatase Monoclonal Antibodies

The melanoma antigen gp75 is the human homologue of the mouse b (brown) locus gene product.

Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin

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