Tumor‐targeting properties of antibody–vascular endothelial growth factor fusion proteins

Halin, Cornelia; Niesner, Uwe; Villani, Maria Elena; Zardi, Luciano; Neri, Dario

doi:10.1002/ijc.10674

Cited by 56 publications

(31 citation statements)

References 52 publications

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“…IL12-L19-TNFa), or with antibody derivatives characterized by extreme isoelectric point values (L19-VEGF164, L19-Calmodulin, L19-Tat), in spite of complete retention of immunoreactivity in vitro. [86][87][88] The use of human antibody derivatives greatly facilitates the clinical development of novel antibody-based biopharmaceuticals, but may hinder certain preclinical and toxicological investigations, as repeated dosing of fusion protein of human origin in rodents can be strongly immunogenic. The acute treatment of tumor-bearing animals with L19 derivatives has led to impressive tumor growth retardations, and in some models, to cancer cures.…”

Section: Discussionmentioning

confidence: 99%

Fibronectin as target for tumor therapy

2005

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During cancer progression, the extracellular matrix (ECM) of the tissue in which the tumor grows is extensively remodeled, both by degradation of preexisting ECM molecules and by the neosynthesis of ECM components, which in many cases are not present in the ECM of normal tissues. Fibronectin (FN), a class of highmolecular-weight adhesive glycoproteins, plays a prominent role in mediating ECM function, because of its high abundance and its interaction with cellular components. Furthermore, the generation of tumor-associated FN isoforms allows the development of specific ligands (e.g., antibodies), which can be used for the selective delivery of therapeutic agents to the tumor environment. In view of these considerations, it is not surprising that FN is being used as a target for biomolecular intervention, both for the development of inhibitory molecules that block the interaction of FN with integrins and other receptors on the cell surface, and for the development of ligand-based targeted imaging and therapeutic strategies. In this review, we briefly present the essential properties of FN, and we then focus on the therapeutic strategies that are currently in preclinical or clinical development and feature FN as a target, or that are based on FN fragments so as to promote tumor-growth inhibition. ' 2005 Wiley-Liss, Inc.Key words: fibronectin; ECM; angiogenesis; EDB; vascular tumor targeting Tumor-associated extracellular matrix components Neoplastic cells are obviously the most important component of solid tumors, and it is not surprising that most efforts in cancer research focus on the characterization of the properties of tumor cells and of their molecules. However, the role of the tumor stroma (and in particular of its extracellular matrix (ECM) components) is becoming increasingly recognized as an important determinant for the growth and progression of solid tumors.1,2 The extensive remodeling of the normal ECM in tumors proceeds through 2 main processes: (i) degradation of preexisting ECM molecules by a number of hydrolytic enzymes (e.g., proteases) that are produced, activated and/or induced by neoplastic cells, and (ii) neosynthesis of ECM components, which in many cases, are not present (or present at low concentration) in the normal tissues. This tumor ECM may generate a more suitable and possibly more permissive and/or instructive environment for tumor growth and progression. Furthermore, tumor-associated ECM components, which may be produced by tumor cells, stromal cells and/or endothelial cells, often represent ideal targets for biomolecular intervention, as will be illustrated in this review. ECM tumor antigens are in general more abundant and possibly more stable than tumor-associated antigens of the tumor cell surface, thus facilitating tumor imaging and targeted therapeutic applications.Among the most abundant ECM components (such as collagens, tenascins, proteoglycans, glycosaminoglycans and laminin), 1 fibronectins (FNs) play a special role both in terms of their functional properties and becau...

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Section: Discussionmentioning

confidence: 99%

Fibronectin as target for tumor therapy

2005

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“…Such an unfavorable situation has been observed with highly charged polypeptides [81][82][83] with very large fusion proteins [84] and with heavily glycosylated products [85]. Recent biodistribution studies with IL9-based immunocytokines revealed that protein production conditions in mammalian cells could have a profound influence on glycostructures (including sialylation) and on extravasation properties [86].…”

Section: Disease-homing Properties Of Immunocytokinesmentioning

confidence: 99%

Immunocytokines: a novel class of products for the treatment of chronic inflammation and autoimmune conditions

Bootz

Neri

2016

Drug Discovery Today

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Antibody-cytokine fusion proteins, often referred to as immunocytokines, represent a novel class of biopharmaceutical agents that combine the disease-homing activity of certain antibodies with the immunomodulatory properties of cytokine payloads. Originally, immunocytokines were mainly developed for cancer therapy applications. More recently, however, the use of antiinflammatory cytokines for the treatment of chronic inflammatory conditions and to treat autoimmune diseases has been considered. This review analyzes basic principles in the design of immunocytokines and describes the most advanced products in preclinical and clinical development.

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“…The theory behind this technology is identical to the one where antibodies conjugated with toxins, in this case radioactive isotopes, act on cells recognized by the antibody. There are major limitations of antibody-related therapy (linked to toxins, enzymes, radioactive material), for example the antibodies' poor tumor penetration due to their molecular size (Halin et al 2002), the toxicity of nonspecific uptake of antibody in liver and reticuloendothelial system (Halpern et al 1983, Pimm et al 1985, and the need for tumor-specific antigens. There are few antigens specific for cancer cells a(exploited in vaccination therapy) resulting in possible toxicity to other normal cells possessing similar antigens.…”

Section: Toxins Conjugated To Antibodies or Growth Factorsmentioning

confidence: 99%