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Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Daniel Bobo, Kye J. Robinson, Jiaul Islam, Kristofer J. Thurecht, Simon R. Corrie
Ontak®, (Denileukin Diftitox) is an example of an approved engineered fusion protein combining cytotoxic molecules with targeting proteins. It was initially designed to treat the aggressive form of non-Hodgkin’s Peripheral T-cell Lymphomas (PTCL). Ontak®, approved in 2008, is an IL-2 receptor antagonist designed to direct the cytocidal action of diphtheria toxin to cells that overexpress the IL-2 receptor on T-cells. In this case diphtheria toxin may be considered the cytotoxic drug and the engineered IL-2 the delivery platform. IL-2R-targeted therapy appears to be an effective treatment option for PTCL patients. Combination therapy with Ontak® and CHOP (the traditional first-line chemotherapy for the disease) has an overall survival rate of 63.3% as opposed to 32–35% with CHOP alone [59, 60]. Ontak® is not myelosuppressive, nor is it associated with significant organ toxicity. Ontak® represented one of the first actively targeted proteinaceous nanoparticles, but is still a singular protein system. It could be used for a range of hematological tumors, many of which overexpress IL-2R [61].
Bacteria-Derived Alternatives to Live Mycobacterium bovis Bacillus Calmette–Guerin for Nonmuscle Invasive Bladder Cancer Treatment
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Esther Julián, Estela Noguera-Ortega
A fusion protein combining Pseudomonas exotoxin A and transforming growth factor alpha (TP-40) was designed to specifically bind the epidermal growth factor receptor (EGFR), which is overexpressed on BC cells [96]. Although no treatment-associated toxicity was observed in a phase I clinical trial, this fusion protein only conferred advantageous outcomes in carcinoma in situ (CIS) patients and not in Ta/T1 patients [97]. Following a similar strategy, oportuzumab monatox (OM) was created as a fusion of the humanized antibody against the epithelial cell adhesion molecule (EpCAM) and the Pseudomonas exotoxin A. This fusion protein binds to the BC cell surface, is internalized, and drives apoptosis of BC cells [98]. Since EpCAM is mainly expressed in malignant cells and its expression correlates with BC cell grade, as more EpCAM is expressed in higher-grade cells [99], this therapy specifically targets BC cells. This therapy has been administered to BCG-refractory or BCG-intolerant patients in phase I and II trials. The results of the phase I trial showed that the therapy did not cause severe side effects and that it was more effective in T1 and Ta patients than in CIS patients [99]. In the phase II trial, 44% of the patients completely responded but some of them experienced recurrences [100]. In view of these promising results, in May of 2015, a phase III study started to recruit patients in whom BCG failed (NCT02449239).
Lessons learned from the failure of several recent trials with biologic treatment in systemic lupus erythematosus
Published in Expert Opinion on Biological Therapy, 2018
Zdenka Hruskova, Vladimir Tesar
Atacicept (also known as TACI-Ig) is a human fusion protein, combining the TACI receptor with a modified immunoglobulin Fc domain and binding both BLyS and a related B cell cytokine APRIL. Atacicept can affect B-cells, as well as antibody producing plasma cells, and can cause a decrease in IgM and IgG immunoglobulin levels [22]. This drug has been also tested repeatedly in SLE. Whereas atacicept was well tolerated in the early trial, subsequent trial in lupus nephritis was terminated after the enrolment of only six patients, due to an unexpected decline in serum IgG levels and the occurrence of serious infections [23]. In a Phase II/III trial of atacicept in SLE (APRIL-SLE), patients with moderate-to-severe SLE were randomized to atacicept 75 mg, 150 mg or placebo. The high-dose arm was stopped early because of two deaths in this arm, but later analyses suggested efficacy of this dose. However, there was no difference between atacicept 75 mg and placebo in flare rates [24]. A post-hoc analysis revealed that patients with better response might be identified when levels of BAFF and APRIL are measured [25]. In Phase IIb trial comparing atacicept 75 mg, 150 mg or placebo the primary end-point was, again, not met but there was some tendency to improved responses with atacicept, especially in patients with high disease activity or serologically active [26].
Intravenous immunoglobulins modify relapsing membranous glomerulonephritis after kidney transplantation: a case report
Published in Acta Clinica Belgica, 2018
Sanne Steyaert, Jo Van Dorpe, Anne Hoorens, Wim Van Biesen, Steven Van Laecke
A complimentary role of the co-stimulatory blockade of belatacept, however, cannot be excluded. Belatacept is a human fusion protein combining a modified extra-cellular portion of CTLA-4 with the Fc fragment of human IgG1 and inhibits T cell activation 10 times stronger than abatacept [8]. There are some preliminary data concerning the therapeutic potential of abatacept, a co-stimulatory inhibitor that targets the podocytic B7-1 protein (CD80). Abatacept induced a total or partial remission in five patients with relapsing focal segmental glomerulosclerosis (FSGS) in the kidney graft and strong expression of the co-stimulatory molecule B7-1, thereby protecting from beta1-integrin activation, which leads to podocyte migration [9]. The role of the podocyte in glomerular diseases has already been well-established and is the primary target in the onset of IMGN, causing proteinuria secondary to foot process effacement [10]. Very strong staining of B7-1 can, as in FSGS, also be found on the podocytes of patients with IMGN but the clinical use of abatacept could not be validated afterward in FSGS or in other glomerulopathies [9]. The potential role of belatacept seems less likely since the relapse occurred under treatment with it.
The current status of biological treatment for uveitis
Published in Expert Review of Clinical Immunology, 2020
Carla Gaggiano, Jurgen Sota, Stefano Gentileschi, Valeria Caggiano, Salvatore Grosso, Gian Marco Tosi, Bruno Frediani, Luca Cantarini, Claudia Fabiani
Etanercept (ETN) is a fusion protein combining two extracellular ligand-binding domains of the human soluble TNF receptor p75 with the end Fc-fragment of human immunoglobulin G1. Acting as a decoy receptor, the drug inhibits the binding of soluble TNF to membrane TNF receptors; in addition, like the human p75 molecule, it also blocks lymphotoxin and binds to transmembrane TNF activating antibody-dependent cell-mediated cytotoxicity. The Fc-fragment prolongs the half-life of ETN, providing a more sustained biologic activity than the human p75. The posologic scheme for adults is 50 mg SC once a week or 25 mg SC twice a week.