Monoclonal antibody G 250 recognizes a determinant present in renal‐cell carcinoma and absent from normal kidney

Oosterwdk, E.; Ruiter, D. J.; Hoedemaeker, Ph. J.; Pauwels, E. K. J.; Jonas, Udo; Zwartendijk, I.; Warnaar, S. O.

doi:10.1002/ijc.2910380406

Cited by 324 publications

(223 citation statements)

References 13 publications

Supporting

Mentioning

220

Contrasting

Unclassified

Order By: Relevance

“…Thus, we decided to implement our Ab-mediated gene targeting method 7,8 by using G250 mAb, which recognizes a TAA in 95% and 60% of primary or metastatic human RCCs, respectively. 17 The extensive study of this mAb, including two phase I clinical trials, revealed no adverse reactions in the patients treated and showed that G250 mAb was concentrated in RCC tumors after intravenous injections. 18,19 These findings suggested that G250 TAA could be a suitable candidate for cell targeting and gene delivery.…”

Section: Discussionmentioning

confidence: 93%

“…17 A suspension of 5 ϫ 10 5 cells was incubated with G250 mAb, washed three times in cold phosphate-buffered saline (PBS), and subsequently incubated with fluorescein isothiocyanate (FITC)-goat (FabЈ) 2 anti-mouse IgG. The isotype-matched mAb NKTA (IgG1 against T-cell receptor-␣␤ clonotypic determinant) (kindly provided by Dr. Thierry Hercend, Villejuif, France) was used as a negative control.…”

Section: G250 Immunophenotypingmentioning

confidence: 99%

“…For these reasons, TAA-mediated strategies involving TAA targeting should be considered, given the availability of the specific anti-RCC monoclonal Ab (mAb) G250. 17 Indeed, this mAb recognizes a TAA that is present on 95% of primary RCCs and on 60% of metastatic RCCs. Moreover, significant clinical experience has been obtained in two phase I studies with 131 I-labeled mAb G250 to evaluate toxicity, pharmacokinetics, and localization capabilities.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Antibody-mediated endocytosis of G250 tumor-associated antigen allows targeted gene transfer to human renal cell carcinoma in vitro

et al. 1999

View full text Add to dashboard Cite

Specific gene transfer into targeted tumor cells remains a critical issue for the development of systemic gene therapy protocols. With this end in view, we have tested the possibility of selectively directing genes to tumor cells through the recognition of tumor-associated antigens (TAA). This was approached in vitro on four human renal cell carcinoma (RCC) lines by means of the highly specific mouse G250 monoclonal antibody (mAb) chemically conjugated to a plasmid DNA conveying a reporter activity. This mAb directed to a TAA that is present on 95% of primary RCCs and on 60% of metastatic human RCCs was extensively characterized, including during clinical trials. Epifluorescence microscopy analysis indicated that upon specific binding to G250 TAA, G250 mAb alone or conjugated to plasmid DNA was internalized by an active endocytic process and colocalized with the transferrin concentrated in the late recycling perinuclear compartment. We also observed that both unconjugated G250 mAb or G250 mAb conjugated to plasmid DNA remained in the perinuclear region of the cells for Ն20 hours and were not rapidly translocated to lysosomes or recycled to the plasma membrane. In contrast, unconjugated plasmid DNA was not internalized. After transfection of G250 TAA-positive RCC lines with G250 mAb conjugated to a plasmid cDNA encoding mouse interleukin-2, a significant and sustained production of mouse interleukin-2 protein was detected from days 5-15 and was abrogated by inhibiting the internalization process. Altogether, our data showed that endocytosis of G250 TAA should be the basis of gene transfer to RCC, suggesting that targeting of TAA capable of internalization may be the basis of new approaches for designing alternative cancer gene therapy procedures.Key words: Renal cell carcinoma; tumor-associated antigen; endocytosis; antifection; gene therapy.M ost ongoing clinical trials in cancer gene therapy are based primarily on direct intratumoral administration of recombinant vectors and/or on ex vivo cell manipulations. 1 To date, only a few procedures permit cell-or tissue-specific targeting in vivo. This can be achieved with specific viral-based gene delivery systems 2,3 and nonviral approaches through DNA complexed to a ligand capable of binding the surface molecules expressed on the targeted cells. 4 -6 We have developed an approach named antifection that allows specific gene targeting. This technique is based on the use of antibodies (Abs) directed toward cell-specific receptors, which are chemically conjugated to plasmid DNA. This was first validated by using various reporter genes expressed in lymphoid cells, both in vitro and in vivo. 7,8 Recently, we have also reported the successful transfer of interleukin-3 (IL-3)-encoding plasmid DNA linked to anti-CD117 Abs into cultured human primary hemopoietic progenitors. 9 Although most of the ligands examined so far continue to be expressed on nontumor cells, limiting the tumor targeting, several Abs directed to tumor-associated antigen (TAA) present a widely restricted...

show abstract

Section: Discussionmentioning

confidence: 93%

Section: G250 Immunophenotypingmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Antibody-mediated endocytosis of G250 tumor-associated antigen allows targeted gene transfer to human renal cell carcinoma in vitro

et al. 1999

View full text Add to dashboard Cite

show abstract

“…Although initially referred to as MN antigen, it was shortly thereafter identified as a new carbonic anhydrase by the same group (2) and was confirmed to be identical to the tumor marker G250 (named after the antibody with which it was identified) published by Oosterwijk and colleagues (3).…”

Section: Introductionmentioning

confidence: 98%

Therapeutic Mechanism and Efficacy of the Antibody–Drug Conjugate BAY 79-4620 Targeting Human Carbonic Anhydrase 9

Petrul

Schatz

Kopitz

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein that is expressed in many different tumors and yet restricted in normal tissues to the gastrointestinal tract. It is upregulated by hypoxia and correlates with tumor grade and poor survival in several tumor indications. Monoclonal antibodies (mAb) with single digit nanomolar binding affinity for CAIX were derived by panning with the recombinant ectodomain of CAIX against the MorphoSys HUCAL Gold library of human Fabs. Highest affinity Fabs were converted to full-length IgGs and subjected to further characterization based upon their avidity and selectivity for CAIX, their capacity to undergo internalization in CAIX-expressing cell lines, and their selective localization to CAIX-positive human xenografted tumors when administered to mice as fluorescent conjugates. Through this selection process, the 3ee9 mAb was identified, which upon conjugation to monomethyl auristatin E through a self-immolative enzyme-cleavable linker yielded the potent and selective CAIX antibody-drug conjugate CAIX-ADC (BAY 79-4620). In preclinical human xenograft models in mice representing several tumor indications, BAY 79-4620 showed potent antitumor efficacy and in some models showed partial and complete tumor shrinkage even following a single dose. The mechanism of action was shown by histology to involve the sequelae of events typical of antitubulin agents. Efficacy in murine preclinical models correlated semiquantitatively, with CAIX expression levels as determined by immunohistochemistry and ELISA. These preclinical data collectively support the development of BAY 79-4620 for the treatment of cancer patients with CAIX overexpressing tumors. Mol Cancer Ther; 11(2); 340-9. Ó2011 AACR.

show abstract

“…To date only a small number of aberrantly expressed proteins have been associated with RCC. Some of these, such as G250, are cell surface proteins that have been identified by murine Mab (Oosterwijk et al, 1986). Clinical trials are already underway utilising a number of immunotherapeutic modalities targeting the G250 protein in RCC (Lamers et al, 2002;Bleumer et al, 2004).…”

mentioning

confidence: 99%

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

et al. 2005

View full text Add to dashboard Cite

The 5T4 oncofoetal antigen is a heavily glycosylated cell surface protein found on human placental trophoblast and on diverse types of human cancer but is not expressed at significant levels on adult human tissues in health. It therefore satisfies the criteria for a tumour-associated antigen and is an ideal target for the immunotherapy of cancer. We report here that 5T4 is strongly expressed on the majority of renal cell carcinomas and therefore this population of patients is suitable for trials of 5T4-targeted therapies. In particular, we have shown that T cells from renal cell carcinoma patients can be genetically modified to kill 5T4 expressing renal cancer cell lines by introduction of a chimeric-signalling protein. This protein consists of a single chain antibody fragment capable of binding antigen directly at the cell surface and then activating the T cell by virtue of a CD3z-signalling domain. This is a powerful tool that bypasses a number of mechanisms that allow tumours to escape T-cell killing and can be readily scaled up for clinical use.

show abstract

Monoclonal antibody G 250 recognizes a determinant present in renal‐cell carcinoma and absent from normal kidney

Cited by 324 publications

References 13 publications

Antibody-mediated endocytosis of G250 tumor-associated antigen allows targeted gene transfer to human renal cell carcinoma in vitro

Antibody-mediated endocytosis of G250 tumor-associated antigen allows targeted gene transfer to human renal cell carcinoma in vitro

Therapeutic Mechanism and Efficacy of the Antibody–Drug Conjugate BAY 79-4620 Targeting Human Carbonic Anhydrase 9

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

Contact Info

Product

Resources

About