New approaches to antibody therapy

Weiner, Louis M.; Adams, Gregory P.

doi:10.1038/sj.onc.1204000

Cited by 82 publications

(49 citation statements)

References 63 publications

(69 reference statements)

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“…Promising results of several naked mAbs have been reported for solid tumors and for lymphoma (43)(44)(45)(46). Antibodies that directly perturb signaling mechanisms have shown clinical benefit, such as those directed against the extracellular domains of HER-2/neu, epidermal growth factor receptor, and CD20 (47,48). The studies in this article suggest that instead of being directly therapeutic by immune effector or direct cytostatic mechanisms, mAbs against CEACAM6 inhibit migration, invasion, and adhesion, thereby limiting metastasis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Adhesion, Invasion, and Metastasis by Antibodies Targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)

2005

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CEACAM5 and CEACAM6 are overexpressed in many cancers and are associated with adhesion and invasion. The effects of three monoclonal antibodies targeting different epitopes on these antigens (NH 2 -terminal and A1B1 domains shared by CEACAM5 and CEACAM6 and the A3B3 domain restricted to CEACAM5) were evaluated in migration, invasion, and adhesion assays in vitro using a panel of human pancreatic, breast, and colonic cancer cell lines, and in the GW-39 human colonic micrometastasis model in vivo. MN-3 FabV and MN-15 FabV were both effective at inhibiting cell migration. MN-15 FabV treatment inhibited invasion, reducing cell penetration through an extracellular matrix (ECM). MN-3 FabValso decreased invasion but was less effective than MN-15 FabV in four of five cell lines. All three monoclonal antibody (mAb) Fabs decreased adhesion of tumor cells to endothelial cells by 49% to 58%. MN-15 FabV but not MN-3 or MN-14 Fabs induced a decrease in adhesion of three of six cell lines to the ECM protein, fibronectin, but adhesion to vitronectin, laminin, collagen-I, and collagen-IV was not affected. In vivo studies showed that treatment with MN-3 FabV or MN-15 FabV of mice implanted with GW-39 human colonic cancer cells increased their survival (P < 0.025 and P < 0.01, respectively). These studies show that antibody Fabs that target either CEACAM5 or CEACAM6 affect cell migration, cell invasion, and cell adhesion in vitro, and that MN-15 and MN-3 Fabs have antimetastatic effects in vivo, resulting in improved survival of mice with metastases. Thus, blocking the N and A1B1 domains of CEACAM5/CEACAM6 can impede the metastatic process.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Adhesion, Invasion, and Metastasis by Antibodies Targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)

2005

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“…[45][46][47] In most cases, tumor-targeting strategies rely on a good-quality ligand, specific to a tumor-associated antigen. Monoclonal antibodies and their fragments are normally the ligands of choice, since they represent the only general class of binding molecules, which can be rapidly raised against virtually any biomolecular target.…”

Section: Fn Fragments As Delivery Vehiclesmentioning

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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“…IgG is a large protein complex itself (~150 kDa), thus it has slower distribution kinetics and severely limits tissue penetration as compared to small molecules. However, alteration of antibody structure can improve quantitative and selective tumor targeting [73]. This could be achieved by addition of specific peptides that for example allow intracellular penetration, or could assist crossing through the 'blood-brain-barrier' [74].…”

Section: Closing Remarksmentioning

confidence: 99%

Targeting the EGFR Pathway for Cancer Therapy

Johnston¹,

Navaratnam²,

Pitz³

et al. 2006

CMC

172

116

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Abstract:Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, ZD1839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab / Herceptin, Pertuzumab / Omnitarg / rhuMab-2C4, Cetuximab / Erbitux / IMC-C225, Panitumumab / Abenix / ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.

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New approaches to antibody therapy

Cited by 82 publications

References 63 publications

Inhibition of Adhesion, Invasion, and Metastasis by Antibodies Targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)

Inhibition of Adhesion, Invasion, and Metastasis by Antibodies Targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)

Fibronectin as target for tumor therapy

Targeting the EGFR Pathway for Cancer Therapy

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