Expression of the oncofetal ED-B–containing fibronectin isoform in hematologic tumors enables ED-B–targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients

Sauer, Stefanie; Erba, Paola Anna; Petrini, Mario; Menrad, Andreas; Giovannoni, Leonardo; Grana, C.; Hirsch, Burkhard; Zardi, Luciano; Paganelli, Giovanni; Mariani, Giuliano; Neri, Dario; Dürkop, Horst; Menssen, Hans D.

doi:10.1182/blood-2008-06-160416

Cited by 153 publications

(131 citation statements)

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“…The alternatively spliced domains extra domain A (EDA) and extra domain B (EDB) of fibronectin, which are targeted by the F8 and L19 antibodies, respectively, exhibit a high level of conservation among species and are virtually undetectable in normal tissues; however, they are abundantly expressed in the stroma and neovasculature of most aggressive types of human cancers 96,[102][103][104][105][106][107][108][109][110] . Similarly, systematic chemical proteomics studies 107,[111][112][113] have recently shown that another component of the extracellular matrix, periostin, exists in several splice isoforms that are abundantly found in most types of cancers [111][112][113][114] .…”

Section: Sulphonamides As Carbonic Anhydrase Inhibitorsmentioning

confidence: 99%

Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

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1,369

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The growth of solid tumours is characterized not only by the uncontrolled proliferation of cancer cells but also by changes in the tumour environment that support the growth of the neoplastic mass and the metastatic spread of cancer cells to distant sites 1 . The formation of new blood vessels from pre-existing ones (angiogenesis) provides oxygen and nutrients to the tumour, which are essential for tumour growth 2 . A complex dynamic interplay exists between the expanding neoplastic mass and the tumour environment, which is affected by the metabolic requirements of cancer cells and by their products, such as secreted proteins (for example, extracellular matrix components and proteases) and metabolites.Upregulated glucose metabolism is a hallmark of invasive cancers 3 . In normal cells glucose is converted to glucose-6-phosphate and subsequently to pyruvate, which is then oxidized in the mitochondria to carbon dioxide and water; this releases 38 moles of ATP per mole of glucose 3 . However, inadequate oxygen delivery to some regions of tumours leads to hypoxia, which restricts oxidative phosphorylation. As a consequence, hypoxic tumour cells shift their metabolism towards glycolysis so that the pyruvate generated in the first step of the process is reduced to lactate, generating only 2 moles of ATP per mole of glucose. This is a less energy-efficient process but it does not depend on oxygen. Furthermore, glycolysis often persists even after reoxygenation because the obtained metabolic intermediates (that is, lactate and pyruvate) can be used for the biosynthesis of amino acids, nucleotides and lipids, thus providing a selective advantage to proliferating tumour cells. This explains Warburg's observation of high glucose consumption and high lactate production in tumour tissues 3-5 (known as the Warburg effect).Oncogenic metabolism also generates an excess of protons and carbon dioxide, which are kept in equilibrium with carbonic acid by the enzyme carbonic anhydrase 3-9 . Thus, increased glucose metabolism in tumour cells leads to enhanced acidification of the extracellular milieu, which is frequently accompanied by various levels of hypoxia. This phenotype confers a substantial Darwinian growth advantage to tumour cells over normal cells, which undergo apoptosis in response to such an acidic extracellular environment 3 .Tumour cells have evolved various mechanisms to cope with the acidic and hypoxic stress mentioned above. They eliminate acidic catabolites by ion transporters and pumps to preserve a slightly alkaline intracellular pH (pH i ), which is optimal for cell proliferation and tumour survival 3-10 . Acid export leads to a reduction in the extracellular pH (pH e ) to values as low as 6.0 (the usual pH e in tumours is in the range of 6.5-7.0) 3 , which is a salient feature of the tumour microenvironment 3-9 . As well as triggering the overexpression of many proteins involved in glucose metabolism -such as the glucose transporter GLUT1 (also known as SLC2A1) and pH-regulating proteins such as carbonic anhyd...

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Section: Sulphonamides As Carbonic Anhydrase Inhibitorsmentioning

confidence: 99%

Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

Self Cite

1,369

1,269

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“…L19SIP (Philogen S.p.A) was radioiodinated at Azienda Ospedaliera Papa Giovanni XXIII, using a modified chloramine-T method, as described previously (34,35). Briefly, 4 mg of L19SIP were labeled with about 370 MBq of 124 I-iodide [produced by the Advanced Center Oncology Macerata (ACOM), Montecosaro, Macerata, Italy) or 7.4 GBq of 131 I-iodide (GE Healthcare; about 25 mg of chloramine-T for 4 mg of L19SIP; 3-minute reaction time) and purified with a Hiprep 26/10 Desalting Column (GE Healthcare).…”

Section: L19sip Antibody and Radiolabelingmentioning

confidence: 99%

“…as defined by PET) and with a provisional dose to the bone red marrow less than 2 Gy, were then treated with 4,107 MBq/m 2 (111 mCi/m 2 ) of 131 I-radretumab ($4.2 mg of protein). Although the calculation of provisional doses derived from dosimetric 131 I-L19SIP administration has been reported (34,35), here we describe a methodology to accurately determine the expected radretumab RIT doses to the bone red marrow, lesions, and healthy organs after dosimetric administration of 124 I-L19SIP, which was applied to 6 patients in the above-mentioned trial. The study not only indicates that immuno-PET with 124 I-labeled L19SIP allows the determination of accurate dosimetries for radioimmunotherapeutic treatment with 131 I-labeled L19SIP, but it also identifies an unsuspected variability of antibody-uptake in different lesions, even within the same patient.…”

Section: Introductionmentioning

confidence: 99%

“…The molecular weight of L19-SIP in its nonreduced form is approximately 80 kDa. RIT with 131 I-labeled L19SIP (radretumab) has been investigated in a phase I and a subsequent phase I/II dose-finding and efficacy study in patients with a variety of cancers, where 131 I-L19SIP has shown excellent tolerability at radioactive doses as high as 7,400 MBq (200 mCi) with therapeutic benefit for some patients enrolled in the study (34,35). This phase II proofof-concept study (EudraCT no.…”

Section: Introductionmentioning

confidence: 99%

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Radretumab Radioimmunotherapy in Patients with Brain Metastasis: A 124I-L19SIP Dosimetric PET Study

Poli

Bianchi

Virotta

et al. 2013

Cancer Immunology Research

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Radioimmunotherapy (RIT) with 131 I-labeled L19SIP (radretumab; a small immunoprotein format antibody directed against the ED-B domain of fibronectin; $80 kDa molecular weight) has been investigated in several clinical trials. Here, we describe the use of immuno-PET imaging with iodine-124 ( 124 I)-labeled L19SIP to predict doses delivered to tumor lesions and healthy organs by a subsequent radretumab RIT in patients with brain metastases from solid cancer. Bone marrow doses were evaluated both during the diagnostic phase and posttherapy, measuring activities in blood (germanium detector) and whole body (lanthanum bromide detector). Expected doses for radretumab administration (4,107 MBq/m 2 ) were calculated from data obtained after administration of an average of 167 MBq 124 I-L19SIP to 6 patients. To assess lesion average doses, the positron emission tomography (PET) scanner was calibrated for the use of 124 I with an International Electrotechnical Commission (IEC) Body Phantom and recovery coefficients were calculated. The average dose to bone red marrow was 0.21 Gy/GBq, with high correlation between provisional and actual posttherapy doses. Although the fraction of injected activity in normal organs was similar in different patients, the antibody uptake in the neoplastic lesions varied by as much as a factor of 60. Immuno-PET with 124 I-labeled L19SIP offers significant advantages over conventional 131 I imaging, in particular accuracy of dosimetric results. Furthermore, the study indicates that antibody uptake can be highly variable even in different lesions of the same patient and that immuno-PET procedures may guide product development with armed antibodies. Cancer Immunol Res; 1(2); 134-43. Ó2013 AACR.

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“…In particular for diagnostic and therapeutic applications, proteins with a low or inexistent expression in healthy tissues yet can have an important value when overexpressed in cancer. For example, proteins already used as targets for anti-cancer therapies, such as tenascin 28 or fibronectin 29 , were weakly or not expressed in the majority of the healthy organs but were highly expressed in both breast tumor and bone metastasis. Thirteen out of 63 differentially expressed proteins in the bone metastasis and the primary tumor have been previously associated with cell migration and/or tumor aggressiveness.…”

Section: Identification Of Differentially Expressed Proteins In the Pmentioning

confidence: 99%

Differential proteomic analysis of a human breast tumor and its matched bone metastasis identifies cell membrane and extracellular proteins associated with bone metastasis

et al. 2012

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The classical fate of metastasizing breast cancer cells is to seed and form secondary colonies in bones. The molecules closely associated with these processes are predominantly present at the cell surface and in the extracellular space, establishing the first contacts with the target tissue. In this study, we had the rare opportunity to analyze a bone metastatic lesion and its corresponding breast primary tumor obtained simultaneously from the same patient. Using mass spectrometry, we undertook a proteomic study on cell surface and extracellular proteinenriched material. We provide a repertoire of significantly modulated proteins, some with yet unknown roles in the bone metastatic process as well as proteins notably involved in cancer cell invasiveness and in bone metabolism. The comparison of these clinical data with those previously obtained using a human osteotropic breast cancer cell line highlighted an overlapping group of proteins. Certain differentially expressed proteins are validated in the present study using immunohistochemistry on a retrospective collection of breast tumors and matched bone metastases. Our exclusive set of selected proteins supports the set-up of further investigations on both clinical samples and experimental bone metastasis models that will help to reveal the finely coordinated expression of proteins that favor the development of metastases in the bone microenvironment.

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Expression of the oncofetal ED-B–containing fibronectin isoform in hematologic tumors enables ED-B–targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients

Cited by 153 publications

References 44 publications

Interfering with pH regulation in tumours as a therapeutic strategy

Interfering with pH regulation in tumours as a therapeutic strategy

Radretumab Radioimmunotherapy in Patients with Brain Metastasis: A 124I-L19SIP Dosimetric PET Study

Differential proteomic analysis of a human breast tumor and its matched bone metastasis identifies cell membrane and extracellular proteins associated with bone metastasis

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