Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo

Silacci, Michela; Brack, Simon; Späth, Nicolas; Buck, Alfred; Hillinger, Sven; Arni, Stephan; Weder, Walter; Zardi, Luciano; Neri, Dario

doi:10.1093/protein/gzl033

Cited by 97 publications

(77 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, tenascin C splice isoforms are commonly found in the tumour stroma and/or around tumour blood vessels [92][93][94][95][96][97][98] and serve as markers of angiogenesis 99 . The regulation of alternative splicing of tenascin C is complicated by the observation that the extra domain C displays a more restricted pattern of expression than the other domains between A1 and D 100,101 . However, whenever this domain is inserted into the tenascin C molecule (for example, in high-grade astrocytomas), it tends to accumulate around neovascular tumour structures [100][101][102] .…”

Section: Sulphonamides As Carbonic Anhydrase Inhibitorsmentioning

confidence: 99%

“…The regulation of alternative splicing of tenascin C is complicated by the observation that the extra domain C displays a more restricted pattern of expression than the other domains between A1 and D 100,101 . However, whenever this domain is inserted into the tenascin C molecule (for example, in high-grade astrocytomas), it tends to accumulate around neovascular tumour structures [100][101][102] . The A1 domain of tenascin C is the target of the F16 antibody, whereas the 81C6 antibody recognizes domain D.…”

Section: Sulphonamides As Carbonic Anhydrase Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

1,393

1,269

View full text Add to dashboard Cite

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...

show abstract

Section: Sulphonamides As Carbonic Anhydrase Inhibitorsmentioning

confidence: 99%

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

1,393

1,269

View full text Add to dashboard Cite

show abstract

“…This study found strong associations of FNIII-C with high grade astrocytoma and glioblastoma, cerebral cavernomas and lung cancers where the distribution of FNIII-C was consistently associated with tumor stroma, tumor blood vessels and proliferating cells in these tissues. [116][117][118] Likewise, FNIII-B containing tenascin-C isoforms co-localize to laminin-5/g2 in the basement membrane region of oral SCC, where increased expression positively correlates with malignancy grade. 119 Another study revealed by IHC and RT-PCR that invasive urothelial cell carcinoma (UCC) exhibits restricted expression of FNIII-A1/ B or D which is closely associated with tumor blood vessels, invasive tumor stroma and damaged muscle.…”

mentioning

confidence: 99%

Tenascin-C: Form versus function

Giblin

Midwood²

2014

Cell Adhesion & Migration

195

233

View full text Add to dashboard Cite

“…Antigens that are preferentially expressed in the tumor extracellular matrix may be better suited for tumor-targeting applications. In fact, several groups have demonstrated that antibodies specific to components of the extracellular matrix (EDB domain of fibronectin (41), domain C of tenascin C (42), and laminin (6,33)) were capable of selective targeting of neovascular structures in solid tumors. However, it has been shown that antibodies against tumor-associated vascular 8 and L36).…”

Section: Discussionmentioning

confidence: 99%

The Multicompartmental p32/gClqR as a New Target for Antibody-based Tumor Targeting Strategies

Sánchez-Martín

Cuesta

Fogal

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Tumor-associated cell surface antigens and tumor-associated vascular markers have been used as a target for cancer intervention strategies. However, both types of targets have limitations due to accessibility, low and/or heterogeneous expression, and presence of tumor-associated serum antigen. It has been previously reported that a mitochondrial/cell surface protein, p32/gC1qR, is the receptor for a tumor-homing peptide, LyP-1, which specifically recognizes an epitope in tumor cells, tumor lymphatics, and tumor-associated macrophages/ myeloid cells. Using antibody phage technology, we have generated an anti-p32 human monoclonal antibody (2.15). The 2.15 antibody, expressed in single-chain fragment variable and in trimerbody format, was then characterized in vivo using mice grafted subcutaneously with MDA-MB-231 human breast cancers cells, revealing a highly selective tumor uptake. The intratumoral distribution of the antibody was consistent with the expression pattern of p32 in the surface of some clusters of cells. These results demonstrate the potential of p32 for antibody-based tumor targeting strategies and the utility of the 2.15 antibody as targeting moiety for the selective delivery of imaging and therapeutic agents to tumors.The localization of tumors may be accomplished by any of several combinations including computed tomography, ultrasonography, gamma camera examination, and glucose consumption (1, 2). However, targeted localization of the tumors is preferred, mainly using specific probes that bind to tumorassociated cell surface antigens or to markers of angiogenesis expressed by endothelial cells or present in the surrounding extracellular matrix (3-6). Probes that bind to tumor-associated cell surface antigens have some drawbacks (7) such as the heterogeneous expression on the cell surface or the increased serum levels of the antigen as tumors grow, which may act as a trap for the targeting agent. Angiogenesis related targets are readily accessible; however, the relatively low abundance of endothelial cells in tumor tissue makes the molecular imaging of tumor neovessels more challenging. Furthermore, angiogenesis may occur also in a physiological context, thus adding more complexity to the targeting.With these limitations in mind, we hypothesized as an alternative target a marker selectively expressed in different compartments in the tumor area. One targeting agent specific for the tumor but not restricted to the tumor cells is the tumor homing peptide (LyP-1), which strongly and specifically accumulates in the tumor after systemic administration, localizing preferentially associated to lymphatic markers (8 -10). LyP-1-binding protein was characterized as p32 (10), a multiligand and multicompartmental protein that has been independently identified in several contexts and has been named accordingly as SF2P32 (splicing factor SF2-associated protein; 11), HABP-1 (hyaluronic acid binding protein-1; 12), gC1qR (globular domain of C1q receptor; Ref. 13), or HIV TAP (Tatassociated protein; 14). Although p...

show abstract

Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo

Cited by 97 publications

References 14 publications

Interfering with pH regulation in tumours as a therapeutic strategy

Interfering with pH regulation in tumours as a therapeutic strategy

Tenascin-C: Form versus function

The Multicompartmental p32/gClqR as a New Target for Antibody-based Tumor Targeting Strategies

Contact Info

Product

Resources

About