Identification of CD70 as a diagnostic biomarker for clear cell renal cell carcinoma by gene expression profiling, real-time RT-PCR and immunohistochemistry

Diegmann, Julia; Junker, Kerstin; Gerstmayer, Bernhard; Bosio, Andreas; Hindermann, Winfried; Rosenhahn, Julia; Eggeling, Ferdinand von

doi:10.1016/j.ejca.2005.05.005

Cited by 72 publications

(46 citation statements)

References 17 publications

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“…Within the lymphoid system, CD70-CD27 interactions regulates T-and B-lymphocyte functions (19,24,25) and may be involved in maintaining CD8 memory T-cell responses against viral infections (26)(27)(28) as well as allograft rejection mediated by CD8 cells (29). CD70 was recently reported as a biomarker for RCC during the course of this study (30,31). Here, we confirm this observation by showing that whereas most normal tissues are CD70 negative, CD70 is aberrantly expressed in both clear cell and papillary RCC.…”

Section: Introductionsupporting

confidence: 78%

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Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates

et al. 2006

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Metastatic renal cell carcinoma (RCC) is an aggressive disease refractory to most existing therapeutic modalities. Identifying new markers for disease progression and drug targets for RCC will benefit this unmet medical need. We report a subset of clear cell and papillary cell RCC aberrantly expressing the lymphocyte activation marker CD70, a member of the tumor necrosis factor superfamily. Importantly, CD70 expression was found to be maintained at the metastatic sites of RCC. Anti-CD70 antibody-drug conjugates (ADC) consisting of auristatin phenylalanine phenylenediamine (AFP) or monomethyl auristatin phenylalanine (MMAF), two novel derivatives of the anti-tubulin agent auristatin, mediated potent antigendependent cytotoxicity in CD70-expressing RCC cells. Cytotoxic activity of these anti-CD70 ADCs was associated with their internalization and subcellular trafficking through the endosomal-lysosomal pathway, disruption of cellular microtubule network, and G 2 -M phase cell cycle arrest. The efficiency of drug delivery using anti-CD70 as vehicle was illustrated by the much enhanced cytotoxicity of antibodyconjugated MMAF compared with free MMAF. Hence, ADCs targeted to CD70 can selectively recognize RCC, internalize, and reach the appropriate subcellular compartment(s) for drug release and tumor cell killing. In vitro cytotoxicity of these ADCs was confirmed in xenograft models using RCC cell lines. Our findings provide evidence that CD70 is an attractive target for antibody-based therapeutics against metastatic RCC and suggest that anti-CD70 ADCs can provide a new treatment approach for advanced RCC patients who currently have no

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Section: Introductionsupporting

confidence: 78%

“…The frequency of CD70 expression observed in this study is discordant with the recent articles, in which 100% of clear cell RCC (30,31) but only 1 of 19 cases of papillary RCC expressed CD70 (30). This may be due to differences in the immunohistochemical staining methods used as well as the patient populations being sampled.…”

Section: Discussioncontrasting

confidence: 39%

Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates

et al. 2006

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“…When tested for antitumor activity in vitro, we found h1F6-mcMMAF (8) conjugates to be substantially more potent than h1F6-mcMMAF(4) derivatives (Table 1). More generally, the therapeutic benefit provided by auristatin-based antibody-drug conjugates has been shown to directly correlate with drug loading, independent of the antibody context, when tested against various tumor cell lines of hematopoietic origin in vitro (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…In support of this notion, experiments in vitro suggested that h1F6-mcMMAF(8) conjugates were more potent than h1F6-mcMMAF(4) at inducing tumor cell death (Table 1). To evaluate the effect of drug load in vivo, we tested the antitumor effects of h1F6 mcMMAF(4) and h1F6 mcMMAF (8) conjugates in all three RCC models developed. Based on antibody dose levels, both compounds induced similar degrees of tumor growth delay when tested against s.c. implanted 786-O tumors, despite the nominal 2-fold increase in drug equivalents per antibody of the mcMMAF(8) conjugate (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Potent Anticarcinoma Activity of the Humanized Anti-CD70 Antibody h1F6 Conjugated to the Tubulin Inhibitor Auristatin via an Uncleavable Linker

Oflazoglu

Stone

Gordon

et al. 2008

Clinical Cancer Research

111

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Purpose: The antitubulin agent monomethyl auristatin F (MMAF) induces potent antitumor effects when conjugated via protease cleavable linkers to antibodies targeting internalizing, tumor-specific cell surface antigens. Humanized 1F6 (h1F6) is a humanized monoclonal antibody targeting CD70, a member of the tumor necrosis factor family that is expressed on hematologic malignancies and carcinomas. Here, we tested h1F6^maleimidocaproyl (mc) MMAF conjugates, consisting of an uncleavable mc linker, for their ability to interfere with the growth of CD70-positive carcinomas. Experimental Design: To evaluate the optimal drug per antibody ratio, we conjugated either four or eight MMAF molecules to the cysteines that comprise the interchain disulfides of h1F6 and determined antitumor activities in vitro and in xenografted mice. The tumor types tested included glioblastoma, patient-derived renal cell carcinoma (RCC) cell isolates, and standard RCC tumor cell lines. Results: All h1F6-mcMMAF conjugates potently interfered with the growth of all carcinomas in vitro and resulted in complete responses of RCC tumors implanted orthotopically or s.c. in mice. In vitro, h1F6-mcMMAF(8) was generally more potent than h1F6-mcMMAF(4). However, h1F6-mcMMAF(4) displayed equal or better efficacy than h1F6-mcMMAF(8) when administered to tumor-bearing mice. Conclusions: We showed that h1F6-mcMMAF conjugates inhibited the growth of human carcinomas and that increased drug loading, while improving potency in vitro, did not substantially affect the pharmacodynamic and pharmacokinetic properties in vivo. Based on these findings, h1F6-mcMMAF(4), designated SGN-75, has been identified as a potential antibody-drug conjugate for clinical development.

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Proteomic Analysis of Primary and Established Cell Lines for the Investigation of Renal Cell Carcinoma

Craven

Banks

2009

Renal and Urinary Proteomics

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Identification of CD70 as a diagnostic biomarker for clear cell renal cell carcinoma by gene expression profiling, real-time RT-PCR and immunohistochemistry

Cited by 72 publications

References 17 publications

Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates

Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates

Potent Anticarcinoma Activity of the Humanized Anti-CD70 Antibody h1F6 Conjugated to the Tubulin Inhibitor Auristatin via an Uncleavable Linker

Proteomic Analysis of Primary and Established Cell Lines for the Investigation of Renal Cell Carcinoma

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