(2015) Improving target cell specificity using a novel monovalent bispecific IgG design, mAbs, 7:2, 377-389, DOI: 10.1080DOI: 10. /19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 Monovalent bispecific IgGs cater to a distinct set of mechanisms of action but are difficult to engineer and manufacture because of complexities associated with correct heavy and light chain pairing. We have created a novel design, "DuetMab," for efficient production of these molecules. The platform uses knobs-into-holes (KIH) technology for heterodimerization of 2 distinct heavy chains and increases the efficiency of cognate heavy and light chain pairing by replacing the native disulfide bond in one of the C H 1-C L interfaces with an engineered disulfide bond. Using two pairs of antibodies, cetuximab (anti-EGFR) and trastuzumab (anti-HER2), and anti-CD40 and anti-CD70 antibodies, we demonstrate that DuetMab antibodies can be produced in a highly purified and active form, and show for the first time that monovalent bispecific IgGs can concurrently bind both antigens on the same cell. This last property compensates for the loss of avidity brought about by monovalency and improves selectivity toward the target cell.
Visualizing deep-brain vasculature and hemodynamics is key to understanding brain physiology and pathology. Among the various adopted imaging modalities, multiphoton microscopy (MPM) is well-known for its deep-brain structural and hemodynamic imaging capability. However, the largest imaging depth in MPM is limited by signal depletion in the deep brain. Here we demonstrate that quantum dots are an enabling material for significantly deeper structural and hemodynamic MPM in mouse brain in vivo. We characterized both three-photon excitation and emission parameters for quantum dots: the measured three-photon cross sections of quantum dots are 4–5 orders of magnitude larger than those of conventional fluorescent dyes excited at the 1700 nm window, while the three-photon emission spectrum measured in the circulating blood in vivo shows a slight red shift and broadening compared with ex vivo measurement. On the basis of these measured results, we further demonstrate both structural and hemodynamic three-photon microscopy in the mouse brain in vivo labeled by quantum dots, at record depths among all MPM modalities at all demonstrated excitation wavelengths.
The gene product of spleen tyrosine kinase (SYK) has been implicated in the suppression of breast cancer invasion. We previously reported that SYK expression is lost in a subset of breast cancer; primarily by methylation-mediated gene silencing. In our study, we explored the possibility of using a DNA methyltransferase inhibitor, 5-aza-2 -deoxycytidine (AZA), to suppress breast cancer cell invasion by restoring SYK expression. We found that AZA treatment reestablished the expression of SYK(L) that was accompanied by suppression of the invasion capacity of SYK-negative cells. This invasion inhibition was not due to global cellular toxicity since this treatment did not affect overall cell proliferation. This decreased invasiveness by AZA treatment was diminished by piceatannol, a SYK inhibitor, suggesting that SYK play a significant role in AZA-inducible invasion suppression. SYK promoter hypermethylation was found infrequent in pathologically normal mammary tissues or benign lesions (<5%). In contrast, SYK methylation was frequently identified in ductal carcinoma in situ (ϳ45%) and invasive ductal carcinoma (47% in node-negative and 40% in node-positive cases), indicating that the hypermethylation of SYK occurs at a stage prior to the development of invasion phenotypes. All these results suggested a potential use of SYK methylation as a valuable biomarker to detect early cancerous lesions and support the use of AZA as a new reagent to the management of advanced breast cancer. © 2004 Wiley-Liss, Inc. Key words: DNA methylation; breast cancer; spleen tyrosine kinase; invasionThe pathologic features of breast cancer follow a sequential progression through benign proliferative hyperplasia, to hyperplasia with atypia, to carcinoma in situ and eventually to invasive and metastatic disease. 1,2 The clinical manifestation of breast cancer is the progression of disease to stages characterized by local invasion of the auxiliary lymph nodes, followed by metastasis primarily to the lung, bone and liver. Invasion and metastasis are two closely related steps that involve changes in the physical coupling of cells to their microenvironment such as alterations of E-cadherin or -catenin and activation of extracellular proteases. 3,4 The development of local invasion and distant metastasis are strongly associated with low therapeutic efficacy and poor survival. 5,6 The clinical value is thus evident to develop diagnostic biomarkers prior to the establishment of invasive disease and to discover effective treatments.Because of the ineffectiveness of traditional therapeutic measures for breast cancer at its advanced stage, the search for compounds against cancer invasion has long been an intensive research area. Despite continued efforts, no effective measure has been discovered to prevent or treat this type of invasive disease. Targeting some of the most obvious molecules, such as metalloproteinase, has proved ineffective, 7 probably because the metalloproteinase family comprises a large number of highly homologous molecules. Oth...
Rational design of metal-free multifunctional therapeutic reagents offers great opportunities for cancer treatment in the clinic. Here, graphitic carbon nitride (g-C 3 N 4 ) quantum dots embedded in carbon nanosheets (CNQD-CN) are in situ prepared via a one-pot hydrothermal approach with formamide as carbon and nitrogen source. The CNQD-CN not only serves as an excellent near-infrared (NIR) fluorescent marker but also acts as a pH-responsive nanocarrier. Moreover, the CNQD-CN possesses both light-to-heat conversion and singlet oxygen generation capabilities under a single NIR excitation wavelength. Further investigations show that systemic delivery of doxorubicin (DOX) using the multifunctional CNQD-CN nanocarrier under NIR irradiation was highly effective to cause cancer cell apoptosis in vitro and inhibit tumor growth in vivo. CNQD-CN represents a multifunctional therapeutic platform for synchronous cancer imaging and treatment through the synergistic effect of phototherapy and chemotherapy.
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