Comparative immunohistochemistry of L19 and F16 in non-small cell lung cancer and mesothelioma: Two human antibodies investigated in clinical trials in patients with cancer

Pedretti, Marta; Soltermann, Alex; Arni, Stephan; Weder, Walter; Neri, Dario; Hillinger, Sven

doi:10.1016/j.lungcan.2008.07.013

Cited by 48 publications

(36 citation statements)

References 53 publications

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“…These clinical development activities are supported by the fact that the F8 antibody recognizes the human and murine cognate antigen with identical affinity, and by the observation that the EDA domain of fibronectin is strongly expressed in a variety of different malignancies. 11,12,[48][49][50] The therapeutic potential of F8-IL4 may deserve to be explored also in nononcological conditions. While the EDA domain of fibronectin is virtually undetectable in most normal adult tissues (with the exception of the female reproductive system), the F8 antibody has been shown to efficiently target endometriosis 8 and atherosclerosis 49 in vivo.…”

Section: Discussionmentioning

confidence: 99%

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The antibody‐based targeted delivery of interleukin‐4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancer

Hemmerle

Neri

2013

Intl Journal of Cancer

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Preclinical studies with recombinant murine interleukin 4 (IL4) in models of cancer have shown potent tumor growth inhibition. However, systemic administration of human IL4 to cancer patients exhibited modest antitumor activity and considerable toxicities. To improve the therapeutic index and reduce side effects of this cytokine, we developed of a novel "immunocytokine" based on sequential fusion of murine IL4 with the antibody fragment F8 (specific to the alternatively spliced extra-domain A of fibronectin, a marker for tumor-angiogenesis) in diabody format. The resulting fusion protein, termed F8-IL4, retained full antigen-binding activity and cytokine bioactivity and was able to selectively localize on solid tumors in vivo. When used as single agent, F8-IL4 inhibited tumor growth in three different immunocompetent murine cancer models (F9 teratocarcinoma, CT26 colon carcinoma and A20 lymphoma). Furthermore, F8-IL4 showed synergistic effects when coadministered with immunocytokines based on IL2 and IL12. Indeed, combination therapy with an IL12-based immunocytokine yielded complete tumor eradication, in spite of the fact that IL4 and IL12 display opposite immunological mechanisms of action in terms of their polarization of T-cell based responses. No weight loss or any signs of toxicity were observed in treated mice, both in monotherapy and in combination, indicating a good tolerability of the immunocytokine treatment. Interestingly, mice cured from CT26 tumors acquired a durable protective antitumor immunity. Depletion experiments indicated that the antitumor activity was mediated by CD81 T cells and by NK cells.Cytokines are potent modulators of the activity of the immune system, which can be used for therapeutic purposes. A number of cytokines (e.g., IL2, interferon-alpha and TNF) are frequently used for the treatment of cancer patients, but these agents can be toxic even at low doses (i.e., few milligrams), preventing the escalation to therapeutically active regimens.1 The antibody-based targeted delivery of cytokines ("immunocytokines") to the site of disease represents a promising avenue for increasing the therapeutic index of cytokine products, increasing activity and sparing normal organs.2 Proinflammatory immunocytokines (e.g., those based on IL2, IL12, IL15 and TNF) often display a potent antitumoral effect in mouse models of cancer.3-7 By contrast, antiinflammatory immunocytokines (e.g., those based on IL10) confer a therapeutic benefit in mouse models of chronic inflammatory conditions (rheumatoid arthritis and endometriosis 8,9 ) but have no impact on tumor growth (Trachsel and Neri, unpublished results).We have mainly used antibodies specific to splice-isoforms of fibronectin and of tenascin-C as vehicles for pharmacodelivery applications, as these antigens are virtually undetectable in the normal healthy adult (exception made for placenta, endometrium and some vessels in the ovaries) while being strongly expressed in the majority of solid tumors and lymphomas, with a prominent vascular staining p...

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Section: Discussionmentioning

confidence: 99%

“…[10][11][12] In particular, we have used the F8, L19 and F16 antibodies 10,13,14 for the development of armed antibodies, some of which have begun clinical testing in oncology and in rheumatology. 15,16 The tumor targeting properties of these antibodies have been documented in mouse models of cancer and in patients.…”

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confidence: 99%

The antibody‐based targeted delivery of interleukin‐4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancer

Hemmerle

Neri

2013

Intl Journal of Cancer

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“…In normal tissues and at pH i values of around 7.0, cells typically produce the 'small' tenascin C splice isoform, which does not include domains A1 to D. When cells are artificially exposed to basic pH values -for example, in cell culture experiments, fetal tissues (which typically have basic pH values of around 7.4-7.5 units) or in aggressive forms of cancer -changes of 0.2-0.3 pH units in the pH i value lead to a complete switch towards the formation of the 'large' tenascin C splice isoform, which includes domains A1 to D 11,12 . 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 .…”

Section: Sulphonamides As Carbonic Anhydrase Inhibitorsmentioning

confidence: 99%

“…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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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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“…When this antibody, in the small immunoprotein (SIP) format (only comprising the variable regions of the antibody to avoid complications with elimination), was injected into a mouse with a tumor derived from xenografted human glioblastoma cells, it was noted that the antibody accumulated selectively in the tenascin-C rich tumor but not in other parts of the body suggesting a good in vivo specificity 30 encouraging to exploit the possibility whether this antibody detects tenascin-C expression in human cancer tissue. Indeed, the F16-SIP recognized tenascin-C in several human cancer types such as in glioblastoma multiforme 31 (GBM), lymphoma, 32 renal cell carcinoma, 33 lung cancer, 34 head and neck cancer 35 and melanoma 36 which altogether suggested a broad application potential of this antibody. Subsequently the antibody was coupled to interleukin-2 (IL2; now available as Proleukin TM ) with the aim to direct immune cells into the tumor for facilitating tumor destruction by the immune system.…”

Section: Nct01403285mentioning

confidence: 99%