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FDA approved the first antibody-mediated cancer radioimmunotherapy

Antibody Guided Precision Radiation Therapy

Abstract: Magic bullets armed with nuclear war head? Monoclonal antibodies labeled with radioactive isotope, when taken orally, seek and attach to tumor cells and bring radiation close to a range of destruction. ... Read more

Targeted Therapy -- Zevalin

Zevalin is the nuclear-armed version of Rituxan. Specifically, Zevalin is the anti-CD20 monoclonal antibody drug Rituxan (”guiding missile”) labeled with the radioactive isotope Yttrium-90 (nuclear “warhead”).

Zevalin is indicated for relapsed or refractory B-cell non-Hodgkin’s lymphoma, including patients with Rituxan-refractory B-cell non-Hodgkin’s lymphoma.

When Zevalin binds to cancer cells and normal mature B cells that express the biomarker protein CD20, it brings radiation to these cells in a harm’s way. Zevalin kills its target cells via both cold (means by which Rituxan does its job) and hot (pin-point radiation) approaches.

Zevalin is given to a patient by intravenous infusion. Isotope Yttrium-90 emits beta ... Read more

Therapies for Mantle Cell Lymphoma: Current Challenges and a Brighter Future

Abstract: Mantle cell lymphoma (MCL), which accounts for about 6% of non-Hodgkin lymphoma (NHL), is characterized by the chromosomal translocation t(11;14) (q13;q32), resulting in de-regulated expression of cyclin D1. Managing MCL is challenging, because it is incurable with conventional chemotherapy as with indolent NHL, but has a more aggressive natural history. Therapeutic advances have been made in the past decade with the incorporation of targeted therapies into the frontline setting, use of aggressive combination regimens followed by consolidation with high dose therapy and autologous stem cell rescue for a younger population, use of less aggressive combinations in the elderly, and translation of pre-clinical findings to the clinical trial realm with novel agents that hold significant promise in the treatment of this disease. The authors review current standard approaches in the treatment of MCL, and novel findings in the pathogenesis of this disease that may guide the way for further development of modern therapeutic approaches. ... Read more

Targeting B Cells for the Treatment of SLE: The Beginning of the End or the End of the Beginning?

Abstract: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease for which therapeutic advances in immunosuppressive and support therapy have significantly improved survival over the last 5 decades. Unfortunately, SLE still carries substantially increased rates of mortality and end stage renal disease which are even more elevated in younger patients. No new drugs have been approved for SLE in over 50 years. Hence, a lot of hope and excitement has been generated by the development of biological agents designed to eliminate B cells either through direct killing (anti-B cell antibodies such as rituximab) or attrition by inhibition of survival (anti-BLyS/BAFF agents such as belimumab). Indeed a strong rationale for targeting B cells in SLE is supported by the major pathogenic roles they play in SLE through both autoantibody production and multiple antibody-independent functions. These hopes, however, have been darted by the failure of two different phase III randomized placebo-controlled trials of rituximab. Yet, clinicians continue to use rituximab off-label with the belief that it provides significant benefit and can rescue patients with disease that is refractory to current modalities. Moreover, recent positive results of two large controlled trials of belimumab have restored confidence that B cell targeting may after all be of benefit in SLE. In this review we discuss the background and rationale for the use of anti-B cell agents in SLE, review the available results, and provide models that could help reconcile the opposing results observed in different studies. These models could also help frame the design and evaluation of current and future B cell therapies. ... Read more

New Insight in the Mechanism of Action of Rituximab: The Interferon Signature Towards Personalized Medicine

Abstract: Rheumatoid arthritis (RA) is the most common chronic inflammatory disorder of the musculoskeletal system that may cause permanent joint damage. The disease has a major impact on the quality of life of affected individuals, costs for the health care system, and society. Currently, no curative treatment is available, and patients are subjected to a prolonged course of treatment. Due to their role in the pathogenesis of RA, B cells have become an attractive target for therapy. Rituximab (Mabthera®/Rituxan®) is a therapeutic monoclonal antibody against CD20 expressed on B cells, which is effective in depleting B cells and approved worldwide for the treatment of RA. Rituximab was shown to be highly beneficial in decreasing clinical symptoms, safe, and well tolerated. However, clinical experience revealed that approximately 30-40% of RA patients do not respond to it. Given the destructive nature of RA, the risk of adverse effects, and considerable costs for therapy, there is a strong need to make predictions on the clinical outcome before the start of therapy. Since nearly all treated patients experience an effective depletion of circulating B cells, questions have been raised concerning the mechanism of action. In this review, novel developments, in particular the findings on the role of the interferon system, will be highlighted. This may add new and important information to our understanding of the mechanism that underlies the clinical outcome of rituximab treatment and may lead to the identification of biomarkers to predict the response. ... Read more

Targeted Therapy -- Rituxan

Rituxan (rituximab) is a genetically engineered chimeric murine-human monoclonal antibody drug that recognizes and binds specifically to the CD20 molecule. CD20 is a protein biomarker displayed on B lymphocytes (B cells for short) — a type of immune cells.

Rituxan was approved by the U.S. FDA for the treatment of B cell non-Hodgkin’s lymphoma (of particular stages and types) and rheumatoid arthritis. About 63,000 new cases of non-Hodgkin’s lymphoma were diagnosed in the U.S. in 2007. There are presently about 2.4 million patients with rheumatoid arthritis in the U.S.

Rituxan targets CD20-expressing non-Hodgkin’s lymphoma B cells and normal mature B cells. It ... Read more

Drug Profile: Bexxar

Other Names: Tositumomab and 131I-Tositumomab.

Makers: Corixa of Seattle, WA and GlaxoSmithKline of Philadelphia, PA.

Disease Treated: Non-Hodgkin’s B-cell lymphoma (NHL). There are currently about 300,000 cases of NHL in the United States, with more than 56,000 new cases predicted to have been diagnosed in 2002. The National Institute of Cancer estimates that approximately 140,000 people have low-grade NHL or transformed low-grade NHL, an aggressive, difficult-to-treat, and particularly deadly form of the disease for which BEXXAR is indicated. The American Cancer Society estimates that 24,400 people would die of non-Hodgkin’s lymphoma in the United States in 2002.

Chemical/Biological Nature: Unlabeled and 131I-labeled murine ... Read more

New drugs approved or recommended for approval

On December 17, 2002, US FDA announced that its Vaccines and Related Biological Products Advisory Committee (VRBPAC) panel has recommended approving MedImmune’s flu vaccine FluMist for use in people of ages 5 to 49. If approved by the full FDA, it would be the first flu vaccine administered by nasal spray, avoiding the shots that could deter some individuals to take the vaccine.

FluMist is a live, attenuated, molecularly engineered vaccine with a tenuous development history (see drug profile on page 10). It has shown better efficacy than ... Read more

Novel Therapeutic Approaches to Chronic Lymphocytic Leukemia Based on Recent Biological Insights

Abstract: Chronic lymphocytic leukemia (CLL) is a malignancy mainly affecting elderly people and is still considered an incurable disease. Despite recent advances in CLL treatment, relapse rates are high and often accompanied by the development of resistance towards conventional chemotherapy. Thus, new agents are needed for the treatment of these patients. In recent years, our understanding of the biological mechanisms driving CLL pathogenesis has considerably improved, and novel treatment strategies are arising. This review summarizes recent insights in CLL biology and describes several new agents and treatment strategies that are currently explored in pre-clinical studies and early-phase clinical trials. ... Read more

Tolerance Induction in Hemophilia A Animal Models: Battling Inhibitors with Antigen-specific Immunotherapies

Abstract: Hemophilia A is an X-linked recessive bleeding disorder due to either a lack of or greatly reduced activity in the blood coagulation protein factor VIII (FVIII), due to mutations in the F8 gene. This poses significant challenges for FVIII replacement therapy since hemophilic patients are not immunologically tolerant to the protein. Thus, a proportion of patients who receive plasma-derived or recombinant FVIII replacement therapy develop anti FVIII neutralizing antibodies, known as "inhibitors." These patients require long-term regimens of high dose FVIII administration, which has varying success rates and prohibitive costs. Therefore, therapeutics for tolerance induction in such patients with inhibitors are desired. In this review, we address the current progress of immunotherapies for inducing FVIII specific tolerance in animal models of hemophilia A. Specifically we discuss the beneficial effects of B-cell depletion on immune tolerance induction (ITI), B-cell mediated gene therapy, antigen-coupled lymphocyte therapy, and regulatory T-cell epitopes (Tregitopes). ... Read more

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