Targeting receptor tyrosine kinases using monoclonal antibodies : the most specific tools for targeted-based cancer therapy

Receptor tyrosine kinases (RTKs) family is comprised of different cell surface glycoproteins. These enzymes participate and regulate vital processes such as cell proliferation, polarity, differentiation, cell to cell interactions, signaling, and cell survival. Dysregulation of RTKs contributes to the development of different types of tumors. RTKs deregulation in cancer has been reported for more than 30 RTKs. Due to critical roles of these molecules in cancer, the specific targeting of RTKs in malignancies is a promising approach. Targeted cellular and molecular therapies have been known as a new type of therapeutics, preventing tumor cell proliferation and invasion by interrupting with molecules necessary for tumor growth and survival. Specific targeting of RTKs using monoclonal antibodies (mAbs) in malignancies as well as in autoimmune disorders is of great interest. The growing number of mAbs approved by the authorities implies on the increasing attentions and applications of these therapeutic tools. Due to the high specificity, mAbs are the most promising substances that target RTKs expressed on the tumor cell surface. In this communication, we review the recent progresses in development of mAbs targeting oncogenic RTKs for cancer treatment.CLL Global Research FoundationManuscrip

Investigating the effect of [C8Py][Cl] and [C18Py][Cl] ionic liquids on the water/oil interfacial tension by considering Taguchi method

Capillary and interfacial forces are of great influences of trapping hydrocarbon in porous media after primary and secondary recovery processes. The trapped crude oil in the reservoir can be mobilized and produced by reducing these forces. Thus, surfactant flooding, as a main enhanced oil recovery (EOR) method, is usually applied to reduce the interfacial tension (IFT) of crude oil–water system in porous medium and improves the oil recovery. This study focused on the effect of [C8Py][Cl] and [C18Py][Cl] ionic liquids (ILs), as a new family of surfactant, in combination with various salts including sodium chloride, potassium chloride, magnesium sulfate and potassium sulfate on IFT reduction. EOR injection solutions were prepared from mixing the ILs at different concentrations of 100, 250, 500 and 1000 ppm with the salts ranging from 500 to 80,000 ppm. Obtained results showed that the minimum IFT value from both ILs was achieved when the concentration of the ILs was about 1000 g/mL, and the concentrations of KCl, K2SO4, MgSO4 and NaCl were 1000, 2000, 500 and 80,000 ppm, respectively. The minimum IFTs were achieved when NaCl and ILs concentrations were the maximum and MgSO4 concentration was the minimum

Comparative expression profile of orphan receptor tyrosine kinase ror1 in iranian patients with lymphoid and myeloid leukemias

It has recently been shown that ROR1, a member of the receptor tyrosine kinase family, is overexpressed in leukemic B cells of Chronic Lymphocytic Leukemia (CLL) and a subset of Acute Lymphoblastic Leukemia (ALL). In this comparative study the expression profile of ROR1 mRNA was investigated in Iranian patients with CLL and Acute Myelogenous Leukemia (AML) and the results were compared with those previously reported in our Iranian ALL patients. RT-PCR was performed on bone marrow and/or peripheral blood samples of 84 CLL and 12 AML patients. CLL samples were classified into immunoglobulin heavy chain variable region (IGHV) gene mutated (n=55) and unmutated (n=29) and also indolent (n=42) and progressive (n=39) subtypes. ROR1 expression was identified in 94% of our CLL patients, but none of the AML patients expressed ROR1. No significant differences were observed between different CLL subtypes for ROR1 expression. Taken together the present data and our previous results on ROR1 expression in ALL, our findings propose ROR1 as a tumor-associated antigen overexpressed in a large proportion of lymphoid (CLL and ALL), but not myeloid (AML) leukemias. Expression of ROR1 seems to be associated to lineage and differentiation stages of leukemic cells with a potential implication for immunotherapy.Tehran University of Medical Sciences and the Ministry of Health and Medical Education of Iran.Publishe

Folate-conjugated nanoparticles as a potent therapeutic approach in targeted cancer therapy

The selective and efficient drug delivery to tumor cells can remarkably improve different cancer therapeutic approaches. There are several nanoparticles (NPs) which can act as a potent drug carrier for cancer therapy. However, the specific drug delivery to cancer cells is an important issue which should be considered before designing new NPs for in vivo application. It has been shown that cancer cells over-express folate receptor (FR) in order to improve their growth. As normal cells express a significantly lower levels of FR compared to tumor cells, it seems that folate molecules can be used as potent targeting moieties in different nanocarrier-based therapeutic approaches. Moreover, there is evidence which implies folate-conjugated NPs can selectively deliver anti-tumor drugs into cancer cells both in vitro and in vivo. In this review, we will discuss about the efficiency of different folate-conjugated NPs in cancer therapy.NoneManuscrip

Nanoparticles and targeted drug delivery in cancer therapy

Surgery, chemotherapy, radiotherapy, and hormone therapy are the main common anti-tumor therapeutic approaches. However, the non-specific targeting of cancer cells has made these approaches non-effective in the significant number of patients. Non-specific targeting of malignant cells also makes indispensable the application of the higher doses of drugs to reach the tumor region. Therefore, there are two main barriers in the way to reach the tumor area with maximum efficacy. The first, inhibition of drug delivery to healthy non-cancer cells and the second, the direct conduction of drugs into tumor site. Nanoparticles (NPs) are the new identified tools by which we can deliver drugs into tumor cells with minimum drug leakage into normal cells. Conjugation of NPs with ligands of cancer specific tumor biomarkers is a potent therapeutic approach to treat cancer diseases with the high efficacy. It has been shown that conjugation of nanocarriers with molecules such as antibodies and their variable fragments, peptides, nucleic aptamers, vitamins, and carbohydrates can lead to effective targeted drug delivery to cancer cells and thereby cancer attenuation. In this review, we will discuss on the efficacy of the different targeting approaches used for targeted drug delivery to malignant cells by NPs

Application of nanomedicine for crossing the blood–brain barrier: Theranostic opportunities in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease characterized with immunopathobiological events, including lymphocytic infiltration into the central nervous system (CNS), microglia activation, demyelination and axonal degeneration. Although several neuroprotective drugs have been designed for the treatment of MS, complete remission is yet matter of debate. Therefore, development of novel therapeutic approaches for MS is of a high priority in immunological research. Nanomedicine is a recently developed novel medical field, which is applicable in both diagnosis and treatment of several cancers and autoimmune diseases. Although there is a marked progress in neuroimaging through using nanoparticles, little is known regarding the therapeutic potential of nanomedicine in neurological disorders, particularly MS. Moreover, the majority of data is limited to the MS related animal models. In this review, we will discuss about the brain targeting potential of different nanoparticles as well as the role of nanomedicine in the diagnosis and treatment of MS and its animal model, experimental autoimmune encephalomyelitis

The skewed balance between regulatory T cells and Th17 in chronic lymphocytic leukemia

While Tregs maintain self-tolerance and inhibit antitumor responses, T helper (Th)17 cells may enhance inflammatory and antitumor responses. The balance between these two important T-cell subsets has been skewed in many immunopathologic conditions such as autoimmune and cancer diseases. B-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the western world and is characterized with monoclonal expansion of B lymphocytes. There is evidence which implies that the progression of CLL is associated with expansion of Treg and downregulation of Th17 cells. In this review, we will discuss about immunobiology of Treg and Th17 cells and their role in immunopathogenesis of CLL as well as their reciprocal changes during disease progression.Tehran University of Medical Sciences, Tehran, IranManuscrip

CD73 as a potential opportunity for cancer immunotherapy

Introduction: Cancer cells apply various mechanisms to induce and enhance immune escape. The complex network of immune-response modulating factors in the tumor microenvironment is a reason for the difficulties encountered when attempting to treat many cancers. Adenosine is a potent immune-modulating factor that can be generated through the degradation of ATP by cooperative action of NTPDase1 (CD39) and ecto-5ʹ-nucleotidase (CD73) molecules. Overexpression of CD73 on tumor and immune cells leads to the presence of a high concentration of this factor in the tumor region. Upregulation of CD73 is associated with the overproduction of adenosine; it suppresses antitumor immune responses and helps proliferation, angiogenesis, and metastasis. Areas covered: We attempt to clarify the immunobiology of CD73 in association with its role in cancer development, angiogenesis, and metastasis. Moreover, we have reviewed CD73-targeting studies and highlighted CD73 as a potent target for cancer immunotherapy. Expert opinion: It seems that blockade of CD73, in combination with immune checkpoint inhibitors such as anti-PD-L1 and anti-CTLA-4, can be a novel promising therapeutic strategy that can be evaluated in the future trials

Construction of a hepatitis B virus neutralizing chimeric monoclonal antibody recognizing escape mutants of the viral surface antigen (HBsAg)

Hepatitis B virus (HBV) infection is a global burden on the health-care system and is considered as the tenth leading cause of death in the world. Over 248 million patients are currently suffering from chronic HBV infection worldwide and annual mortality rate of this infection is 686000. The “a” determinant is a hydrophilic region present in all antigenic subtypes of hepatitis B surface antigen (HBsAg), and antibodies against this region can neutralize the virus and are protective against all subtypes. We have recently generated a murine anti-HBs monoclonal antibody (4G4), which can neutralize HBV infection in HepaRG cells and recognize most of the escape mutant forms of HBsAg. Here, we describe the production and characterization of the chimeric human-murine antibody 4G4 (c-4G4). Variable region genes of heavy and light chains of the m-4G4 were cloned and fused to constant regions of human kappa and IgG1 by splice overlap extension (SOE) PCR. The chimeric antibody was expressed in Chinese Hamster Ovary (CHO)-K1 cells and purified from culture supernatant. Competition ELISA proved that both antibodies bind the same epitope within HBsAg. Antigen-binding studies using ELISA and Western blot showed that c-4G4 has retained the affinity and specificity of the parental murine antibody, and displayed a similar pattern of reactivity to 13 escape mutant forms of HBsAg. Both, the parental and c-4G4 showed a comparably high HBV neutralization capacity in cell culture even at the lowest concentration (0.6μg/ml). Due to the ability of c-4G4 to recognize most of the sub-genotypes and escape mutants of HBsAg, this antibody either alone or in combination with other anti-HBs antibodies could be considered as a potent alternative for Hepatitis B immune globulin (HBIG) as an HBV infection prophylactic or for passive immunotherapy against HBV infection