Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250.

Steffens, M.G.; Boerman, Otto C.; Oosterwijk-Wakka, J.C.; Oosterhof, G.O.N.; Witjes, J.A.; Koenders, E.B.; Oyen, W.J.G.; Buijs, W.C.A.M.; Debruyne, F.M.J.; Corstens, F.H.M.; Oosterwijk, Egbert

doi:10.1200/jco.1997.15.4.1529

Cited by 153 publications

(150 citation statements)

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“…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. Indeed, due to the poor efficiency of conventional treatments, 32 the design of new strategies remains a major issue in the therapy of RCC.…”

Section: Discussionmentioning

confidence: 93%

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

et al. 1999

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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...

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Section: Discussionmentioning

confidence: 93%

“…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. 18,19 These studies have established the lack of cross-reactivity with normal tissues, with the exception of cells of the larger bile ducts and gastric mucosal cells.…”

mentioning

confidence: 97%

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

et al. 1999

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“…CA9 is a known antigen currently being targeted for RCC immunotherapy (Divgi et al, 1998;Steffens et al, 1999;Uemura et al, 1999;Grabmaier et al, 2000;Li et al, 2001;Bui et al, 2003;Kennett, 2003). To compare expression of CD70 with CA9, we performed real-time quantitative RT -PCR analysis on multiple normal tissues and clinical RCC samples (Figure 7).…”

Section: Cd70 Exhibits a More Restricted Normal Tissue Distribution Amentioning

confidence: 99%

“…An example of an antigen found to be overexpressed in RCC is carbonic anhydrase IX (CA9), which is the target for the monoclonal antibody (mAb) G250 (Pastorek et al, 1994;Uemura et al, 1999;Grabmaier et al, 2000;Li et al, 2001;Bui et al, 2003). Immunoscintigraphy of RCC patients dosed with iodine-131-labelled G250 demonstrated tumour targeting to metastatic sites (Divgi et al, 1998;Steffens et al, 1999;Kennett, 2003).…”

mentioning

confidence: 99%

CD70 (TNFSF7) is expressed at high prevalence in renal cell carcinomas and is rapidly internalised on antibody binding

Pj¹,

Ja²,

Steers

et al. 2006

Br J Cancer

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In order to identify potential markers of renal cancer, the plasma membrane protein content of renal cell carcinoma (RCC)-derived cell lines was annotated using a proteomics process. One unusual protein identified at high levels in A498 and 786-O cells was CD70 (TNFSF7), a type II transmembrane receptor normally expressed on a subset of B, T and NK cells, where it plays a costimulatory role in immune cell activation. Immunohistochemical analysis of CD70 expression in multiple carcinoma types demonstrated strong CD70 staining in RCC tissues. Metastatic tissues from eight of 11 patients with clear cell RCC were positive for CD70 expression. Immunocytochemical analysis demonstrated that binding of an anti-CD70 antibody to CD70 endogenously expressed on the surface of A498 and 786-O cell lines resulted in the rapid internalisation of the antibody -receptor complex. Coincubation of the internalising anti-CD70 antibody with a saporin-conjugated secondary antibody before addition to A498 cells resulted in 50% cell killing. These data indicate that CD70 represents a potential target antigen for toxin-conjugated therapeutic antibody treatment of RCC.

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“…48 -50 For a few murine antibodies, replacement of the C regions of the light and heavy chains by human C regions may not provide the solution to the problem of reducing HAMA responses in patients, because the V regions are potentially immunogenic and can lead to the development of antiidiotypic antibodies in patients. [47][48][49][50] Therefore, other approaches for reducing the immunogenicity of murine MAbs have been sought. The murine V regions can be genetically humanized by the grafting of CDRs into human framework regions.…”

Section: Analysis Of Immunogenicity Of Cc49 Scfvsmentioning

confidence: 99%

Effects of humanization and gene shuffling on immunogenicity and antigen binding of anti-tag-72 single-chain Fvs

Pavlínková

Colcher²,

Booth

et al. 2001

Int. J. Cancer

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Key words: antibody engineering; antigen binding; antiidiotypic antibodies; monoclonal antibodies; single-chain antibodiesOne of the major complications in the clinical application of monoclonal antibodies can be the development of a human antimurine antibody (HAMA) response in patients. The HAMA can alter the clearance rate of the administered antibody from serum and can produce allergic reactions in patients. 1,2 The HAMA response can be directed against (i) mouse-specific determinants on the C region of heavy and light chains (antiallotypic Ig), (ii) isotypic determinants on the C region of heavy chains (antiisotypic Ig) and (iii) determinants specific for the administered mouse Ig (antiidiotypic Ig). 3 Many murine monoclonal antibodies (MAbs) have been humanized to overcome the HAMA response in patients. Two methods are being used for the genetic humanization of MAbs: chimerization, in which non-human C regions are replaced by C human regions 4 and complementary determining region (CDR) grafting, in which human CDRs are replaced by murine CDRs on the human framework regions. 5 The humanized MAbs are likely to be less immunogenic; however, murine CDRs are coding for non-human V region sequences and may still elicit an antiidiotypic response. 6 -9 Furthermore, CDR grafting could also generate new immunogenic epitopes. 6,9 The murine MAb CC49 recognizes tumor-associated glycoprotein (TAG-72), which is expressed by most human adenocarcinomas of the pancreas, colon, ovary, prostate, lung and esophagus 10 and is absent in most normal tissues. 11 Radiolabeled CC49 IgG has shown excellent tumor localization in several clinical trials. [12][13][14][15][16] However, one major complication of its clinical use is the development of a HAMA response in patients. 14 The incidence of HAMA response in gastrointestinal and ovarian cancer patients 1 month after exposure to the murine MAb CC49 was 70%. 17 Fifty-four percent of these patients developed an antiidiotypic response, and 12% developed an antiidiotypic response in the absence of antiallotypic and antiisotypic Ig. 17 However, CC49 MAb is less immunogenic than other murine MAbs that have been used in clinical trials. For example, 89%, 100% and 80% of patients receiving the MAbs B72.3, 17 G250 18 and CO17-1A, 19 respectively, developed the HAMA responses.In an attempt to modify the properties of the MAb CC49, genetically engineered CC49 single-chain antibody fragments (scFvs) have been developed. Compared with the corresponding IgG, scFvs exhibited a rapid blood clearance, excellent penetration into the tumor from the vasculature and higher tumor/normal tissue ratios in animal models. 20 -31 We have undertaken new studies to analyze the immunogenicity of CC49 scFvs using human sera obtained from patients with colon cancer treated by CC49 IgG in clinical trials. Three different CC49 scFv constructs (Fig. 1) were compared. The first construct was comprised of mouse CC49 variable light (V L ) and mouse CC49 variable heavy (V H ) regions connected by a 205C linker (m/m scF...

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Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250.

Cited by 153 publications

References 10 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

CD70 (TNFSF7) is expressed at high prevalence in renal cell carcinomas and is rapidly internalised on antibody binding

Effects of humanization and gene shuffling on immunogenicity and antigen binding of anti-tag-72 single-chain Fvs

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