Cancer Therapy with Radiolabeled and Drug/Toxin-conjugated Antibodies

Govindan, Serengulam V.; Griffiths, Gary L.; Hansen, Hans J.; Horak, Ivan D.; Goldenberg, David M.

doi:10.1177/153303460500400406

Cited by 36 publications

(31 citation statements)

References 73 publications

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“…Sometimes, long-term impacts on heart, lung, kidney, or bone marrow occur (British Cancer Agency; http://www.bccancer.bc.ca/default.htm). Exploiting the target specificity of antibodies, which selectively bind to tumor-associated antigens presented on the cell surface, reduces the systemic toxicity of the coupled compounds such as small-molecule drugs, radionuclides, or protein toxins (Govindan et al 2005). Immunotoxins consisting of plant or bacterial toxins such as diphtheria toxin, Pseudomonas exotoxin, ricin, or saponin (with mutated or deleted cell-binding domains to prevent binding to normal cells) fused to cell targeting agents such as antibodies, cell-specific hormones, growth factor ligands, or transferrin have to be internalized to deploy their cell-killing activities (Johannes and Decaudin 2005).…”

Section: Introductionmentioning

confidence: 99%

Natural and engineered ribonucleases as potential cancer therapeutics

Arnold

Ulbrich‐Hofmann

2006

Biotechnol Lett

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By reason of their cytotoxicity, ribonucleases (RNases) are potential anti-tumor drugs. Particularly members from the RNase A and RNase T1 superfamilies have shown promising results. Among these enzymes, Onconase, an RNase from the Northern Leopard frog, is furthest along in clinical trials. A general model for the mechanism of the cytotoxic action of RNases includes the interaction of the enzyme with the cellular membrane, internalization, translocation to the cytosol, and degradation of ribonucleic acid. The interplay of these processes as well as the role of the thermodynamic and proteolytic stability, the catalytic activity, and the capability of the RNase to evade the intracellular RNase inhibitor has not yet been fully elucidated. This paper discusses the various approaches to exploit RNases as cytotoxic agents.

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Section: Introductionmentioning

confidence: 99%

Natural and engineered ribonucleases as potential cancer therapeutics

Arnold

Ulbrich‐Hofmann

2006

Biotechnol Lett

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“…30 More recently, murine mAbs have been modified by genetic engineering, producing chimeric (ch), humanized (hz), and human mAbs, some of which are used for the treatment of cancer. 31 Several targets have been defined for different tumors, including the receptor of tyrosine-kinase type 1 and growth factors receptors, such as HER2/neu, which is overexpressed in gastric, ovarian, and pulmonary cancer and in 30% of invasive breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Melanocortin 1 Receptor Is Expressed by Uveal Malignant Melanoma and Can Be Considered a New Target for Diagnosis and Immunotherapy

López

Pereda

Ramírez

et al. 2007

Invest. Ophthalmol. Vis. Sci.

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“…The development of various linkers which bridge disparate molecules such as small drugs conjugated to tumor-targeting carriers has been the subject of numerous studies for the past few years [ 69,70 ] . Based on numerous prior studies, the incorporation and design of linkers is critical to the success of ADCs.…”

Section: Peptide Linker Designsmentioning

confidence: 99%

Design, Development, and Characterization of Recombinant Immunotoxins Targeting HER2/neu

Cao

Rosenblum

2012

Antibody-Drug Conjugates and Immunotoxins

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BackgroundThe human epidermal growth factor receptor 2 (HER2), also known as ErbB2, c-erbB2, or HER2/neu, was initially discovered in 1985 by two independent laboratories [ 1,2 ] . HER2/neu is a 185 kDa (1,255 aa) transmembrane receptor encompassing an intracellular tyrosine kinase domain and an extracellular ligand binding component [3][4][5] . Extensive clinical studies have shown that overexpression of HER2/neu is found in 20-40% of patients with breast, ovarian, endometrial, gastric, bladder, prostate, and lung cancers. Studies clearly demonstrate that HER2/neu overexpression correlates with the prevalence of metastatic spread of many tumors and is generally considered to be a poor prognostic indicator [6][7][8][9] .Since HER2/neu overexpression by tumor cells is quite speci fi c, therapies directed against this receptor have rapidly gained recognition for their selectivity and ef fi cacy in the clinical setting. While targeting of HER2/neu with humanized antibodies such as trastuzumab (Herceptin; Genentech) has proven to be an effective approach for the treatment of HER2/neu-overexpressing breast cancers, there are a signi fi cant number of patients with HER2/neu-positive tumors who do not respond or who acquire resistance to this therapy [10][11][12][13] . Therefore, there is a need for novel therapeutic approaches using HER2/neu not only as a target for interfering with the growth factor signaling component but also for receptor-mediated delivery of cytotoxic agents.Immunotoxins are a novel approach for the development of highly speci fi c, targeted agents and which generally employ a powerful class of protein toxins [ 14,15 ] . These include plant toxins such as ricin [16][17][18][19][20][21][22][23][24][25] , saporin [26][27][28][29] , and gelonin [30][31][32] Diphtheria toxin (DT) [ 33 ] and Pseudomonas exotoxin (PE) [34][35][36][37][38][39][40][41][42][43] , which ADP ribosylate elongation factor 2 (EIF2). Anti-HER2/neu immunotoxins have been created initially by chemically conjugating an antibody to a whole protein toxin or, for more selective activity, using a protein toxin devoid of its natural binding domain [ 19,23, 30,44 ] . Technical advances in antibody engineering now enable us to produce various antibodies or antibody fragments in Escherichia coli , and as a result, HER2/neu-speci fi c antibodies and engineered fragments thereof have been developed to deliver various toxins to HER2/neu-positive tumor cells [45][46][47][48][49][50][51] . Various anti-HER2/neu immunotoxins which have been developed or are currently under evaluation are described in Table 18.1 . Antibody-Drug Conjugates: Promise and ProblemsAntibody-based therapeutics is of growing signi fi cance for cancer therapy. To date, two of the most promising strategies to enhance the antitumor activity of antibodies are antibody-drug conjugates (ADCs) and antibodies (or fragments) chemically conjugated or genetically fused to various toxins (immunotoxins).One successful application of the ADC approach is Trastuzumab-DM1. This is a cov...

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Cancer Therapy with Radiolabeled and Drug/Toxin-conjugated Antibodies

Cited by 36 publications

References 73 publications

Natural and engineered ribonucleases as potential cancer therapeutics

Natural and engineered ribonucleases as potential cancer therapeutics

Melanocortin 1 Receptor Is Expressed by Uveal Malignant Melanoma and Can Be Considered a New Target for Diagnosis and Immunotherapy

Design, Development, and Characterization of Recombinant Immunotoxins Targeting HER2/neu

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