A phase III study of anti-B4-blocked ricin as adjuvant therapy post-autologous bone marrow transplant: CALGB 9254

Furman, Richard R.; Grossbard, Michael L.; Johnson, Jeffrey L.; Pecora, Andrew L.; Cassileth, Peter A.; Jung, Sin‐Ho; Peterson, Bruce A.; Nadler, Lee M.; Freedman, Arnold S.; Bayer, Ruthee-Lu; Bartlett, Nancy L.; Hurd, David D.; Cheson, Bruce D.; And, For The Cancer Leukemia Group B

doi:10.3109/10428194.2010.543714

Cited by 24 publications

(15 citation statements)

References 24 publications

(18 reference statements)

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“…In the next phase I/II clinical studies with these immunotoxins the partial response was 2/27 and 1/15 for RFT5.dgA and Ki-4.dgA respectively [47]. Moreover, different ricin-based immunotoxins against non-Hodgkin lymphomas (NHL) expressing CD5, CD19, and CD22 antigens have been tested in phase I, II and III clinical trials [49,50]. However, the phase III trials with anti-B4-blocked ricin (anti-B4-bR), directed against the CD19 antigen finally fail to support a role for this immunotoxin as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma [50].…”

Section: Ricin-derived Immunotoxinsmentioning

confidence: 97%

Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro

Słomińska-Wojewódzka

Sandvig

2013

Antibodies

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Ricin is a type II ribosome inactivating protein (RIP) isolated from castor beans. Its high toxicity classifies it as a possible biological weapon. On the other hand, ricin linked to specific monoclonal antibodies or used in other conjugates has powerful medical applications. Ricin consists of an A-chain (RTA) that damages ribosomes and inhibits protein synthesis, and a B-chain that plays a role in binding and cellular uptake. A number of recent studies have demonstrated that ricin-induced inhibition of protein synthesis is not the only mechanism responsible for cell death. It turns out that ricin is able to induce apoptosis in different cell lines and multiple organs in animals. However, the molecular link between protein synthesis inhibition and ricin-dependent triggering of apoptotic cell death is unclear. This review describes the intracellular transport of ricin and ricin-based immunotoxins and their mechanism of action in different non-malignant and cancer cell lines. Moreover, various ricin-containing immunotoxins, their composition, medical applications and side-effects will be described and discussed. Understanding the mechanism of action of ricin-based immunotoxins will facilitate construction of effectively acting immunotoxins that can be used in the clinic for cancer treatment

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Section: Ricin-derived Immunotoxinsmentioning

confidence: 97%

Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro

Słomińska-Wojewódzka

Sandvig

2013

Antibodies

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“…Although the phase I and II trials suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous SCT, the phase III trial results failed to show any connection between anti-B4-bR administration and even free survival of patients. These trials were reported between the years 1993-2011 [116,118,119].…”

Section: Anti-b4-brmentioning

confidence: 99%

Antibody-Based Immunotoxins for the Treatment of Cancer

Becker

Benhar

2012

Antibodies

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Antibody-based immunotoxins comprise an important group in targeted cancer therapeutics. These chimeric proteins are a form of biological guided missiles that combine a targeting moiety with a potent effector molecule. The targeting moiety is mostly a monoclonal antibody (MAb) or a recombinant antibody-based fragment that confers target specificity to the immunotoxin. The effector domain is a potent protein toxin of bacterial or plant origin, which, following binding to the target cells, undergoes internalization and causes cell death. Over time and following research progression, immunotoxins become better fitted to their purpose, losing immunogenic fragments and non-specific targeting moieties. Many immunotoxins have gone through clinical evaluation. Some of these have been shown to be active and work is progressing with them in the form of further clinical trials. Others, mostly developed in the previous century, failed to generate a response in patients, or even caused undesired side effects. This article reviews the antibody and protein-toxin based immunotoxins that were clinically evaluated up to the present day.

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“…The most frequently used toxins in these immunotherapeutic agents originate from plants, like Ricin A, or bacteria, like Pseudomonas exotoxin A (ETA) and Diphtheria Toxin [5,[8][9][10]. A panel of those proteins, especially targeted against cancer cells, has already been investigated in clinical trials [11][12][13]. However, a major drawback of non-human toxins is the potential induction of unwanted immune responses [14].…”

Section: Introductionmentioning

confidence: 99%

Species-Dependent Functionality of the Human Cytolytic Fusion Proteins Granzyme B-H22(scFv) and H22(scFv)-Angiogenin in Macrophages

et al. 2013

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Human cytolytic fusion proteins (hCFPs) are comprised of a specific cell-surface-binding moiety and an effector molecule of human origin. In contrast to common immunotoxins, including bacterial or plant toxins, they are considered not to be immunogenic. Two examples for human pro-apoptotic effector proteins are the serine protease Granzyme B and the RNase Angiogenin. Pre-clinical testing of functionality in in vitro and in vivo studies is essential for therapeutics. Establishing relevant animal models that have predictive value for therapeutic success is a great challenge in biomedical research. In this study, we investigated the species-dependent cytotoxic activity of two hCFPs prior to their application in a murine inflammation model. We found that in vitro and ex vivo either hCFP was able to kill human cells only, leaving murine cells unaffected. In contrast, no species-dependency was found for the bacterial Pseudomonas exotoxin A based immunotoxin H22(scFv)-ETA'. This species-dependent functioning has to be carefully considered when performing pre-clinical studies in animal models.

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A phase III study of anti-B4-blocked ricin as adjuvant therapy post-autologous bone marrow transplant: CALGB 9254

Cited by 24 publications

References 24 publications

Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro

Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro

Antibody-Based Immunotoxins for the Treatment of Cancer

Species-Dependent Functionality of the Human Cytolytic Fusion Proteins Granzyme B-H22(scFv) and H22(scFv)-Angiogenin in Macrophages

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