Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells

Breast and ovarian cancer are two of the leading causes of cancer deaths among women in the United States. Overexpression of the HER2/neu oncoprotein has been reported in patients affected with breast and ovarian cancers, and is associated with poor prognosis. To develop a novel targeted therapy for HER2/neu expressing tumors, we have constructed a fully human IgE with the variable regions of the scFv C6MH3-B1 specific for HER2/neu. This antibody was expressed in murine myeloma cells and was properly assembled and secreted. The Fc region of this antibody triggers in vitro degranulation of rat basophilic cells expressing human FcεRI (RBL SX-38) in the presence of murine mammary carcinoma cells that express human HER2/neu (D2F2/E2), but not the shed (soluble) antigen (ECDHER2) alone. This IgE is also capable of inducing passive cutaneous anaphylaxis in a human FcεRIα transgenic mouse model, in the presence of a cross-linking antibody, but not in the presence of soluble ECDHER2. Additionally, IgE enhances antigen presentation in human dendritic cells and facilitates cross-priming, suggesting that the antibody is able to stimulate a secondary T-cell anti-tumor response. Furthermore, we show that this IgE significantly prolongs survival of human FcεRIα transgenic mice bearing D2F2/E2 tumors. We also report that the anti-HER2/neu IgE is well tolerated in a preliminary study conducted in Macaca fascicularis (cynomolgus) monkeys. In summary, our results suggest that this IgE should be further explored as a potential therapeutic against HER2/neu overexpressing tumors, such as breast and ovarian cancers.Fil: Daniels, Tracy R.. University of California at Los Angeles; Estados UnidosFil: Leuchter, Richard K.. University of California at Los Angeles; Estados UnidosFil: Quintero, Rafaela. University of California; Estados UnidosFil: Helguera, Gustavo Fernando. University of California at Los Angeles; Estados Unidos. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodríguez, José A.. University of California at Los Angeles; Estados UnidosFil: Martínez Maza, Otoniel. University of California at Los Angeles; Estados UnidosFil: Schultes, Birgit C.. Advanced Immune Therapeutics, Inc.; Estados Unidos. Momenta Pharmaceuticals, Inc.; Estados UnidosFil: Nicodemus, Christopher F.. Advanced Immune Therapeutics, Inc.; Estados UnidosFil: Penichet, Manuel L.. University of California at Los Angeles; Estados Unido

Social bookmarking in the enterprise

In this practitioner-oriented overview of a pilot project at a medium-sized software company, we outline the early phases of an effort to implement a Social Bookmarking System (SBS) within an enterprise. In particular, we discuss some of the unexpected challenges encountered with regards to potential user adoption, and the design strategy we used to address those challenges. 1. Introduction: Findability in the enterprise intranet has become an increasing critical issue with the growth in size and complexity of corporate information environments. To date, much of the solution space has focused on approaches such as the construction of rich, domain specific taxonomies and the development of sophisticated full-text search algorithms [1]. These methods can be extremely expensive and require careful ongoing maintenance to succeed. While they have proved valuable, some organizations, are beginning to seek out new innovations [2]. Social Bookmarking Systems (SBS) are a class of collaborative applications that allow users to save, access, share and describe shortcuts to web resources. Initially conceived as personal information management tools, they were designed to function as centralized storage repositories to simplify the collection of bookmarks for users who browse the Internet with more than one machine in different locations. Later, systems such as the now archetypical del.icio.us [3] added two key features: 1) description of bookmarks with arbitrary free keywords (â taggingâ ), and 2) sharing of bookmarks and tags across users. We decided to undertake a small pilot project within our own enterprise to determine whether an SBS might aid in refindability, term extraction, and identification of communities of practice. Recent technology experiments such as IBMâ s Dogear [4] have suggested some promise for del.icio.us-style systems inside the corporate firewall. 2. Assessing User Readiness: One of the attractive features of social software is that they tend to be inexpensive to implement from a technical standpoint. However, because their success relies entirely on user participation, the organizational cost can be quite high. Therefore, instead of moving directly into implementation, we first conducted a user survey and series of interviews to both validate the deficiency in existing information retrieval mechanisms and gauge the receptivity to bookmarking as a possible solution. Rather than definitive data about user attitudes towards tagging, we found it difficult to elicit constructive feedback because most users â even those familiar with existing systems such as del.icio.us â did not fundamentally understand core social bookmarking concepts. 3. Communicating Concepts to Users: Based on our initial findings, we modified our project plan to focus efforts on user education. We employed a non-traditional design approach in which we identified the central features of an SBS, mapped those features to user activities, and then translated the activity scenarios into graphical comics. In architecting complex systems, comics can more effectively communicate concepts by abstracting away technical details such as the user interface. [5] 4. Future Work and Implications: This education strategy is incorporated into the roadmap for the future phases of the project that also includes milestones related to technical extensibility, data collection, and internal marketing to drive usage. We believe that the most critical aspect of implementing social classification within an enterprise context may be preparing users to both understand and embrace tagging as a conceptual framework

Social Bookmarking in the Enterprise

Findability on enterprise intranets has become an increasingly critical issue with the growth i

WIGNER DVR: A NEW METHOD FOR THE CALCULATION OF VRT DYNAMICS OF VAN DER WAALS CLUSTERS

$^{1}$R. J. Saykally and G. A. Blake, Science, 1993, 259, 1570-1575 $^{2}$M.J. Elrod and R.J. Saykally, in press, Journal of Chemical Physics $^{1}$C. LeForestier, JCP, 1994, 101, 7357-7363Author Institution: University of California, Berkeley, CA 94720; Universite Paris-Sud, Batiment 490, 91405 Orsay, France.Given the existence of a large body of precise spectroscopic data for weakly bound $complexes^{1}$, the determination of multidimensional intermolecular potential energy surfaces (IPS's) has been limited by available computer technology and computational techniques. Due to these limitations, the most complex IPS that has been fitted to date is that for the 4-D $(HCl)_{2}.^{2}$ New dynamics methods have recently been developed for the efficient evaluation of the hamiltonian using a Wigner $DVR^{3}$ (discrete variable representation). This new technique has been applied to the 4-D $(HCl)_{2}$ and was combined with the complementary Lanczos algorithm for efficient diagonalization of the resulting matrix. The accuracy is comparable to that of the variational technique. The time requirements of these new methods were compared with those of Elrod and Saykally for the $(HCl)_{2}$ and found to be reduced by more than half., whereas, memory limitations were virtually eliminated. Following these encouraging results, these methods are being applied to the 6-D $(HF)_{2}$

VIBRATION-ROTATION-TUNNELING-SPECTROSCOPY OF (H2O)4(H_{2}O)_{4} AND (H2O)5(H_{2}O)_{5}: THE DRAMATIC EFFECT OF SYMMETRY ON HYDROGEN BOND TUNNELING DYNAMICS

$^{a}$ K. Liu, M.G. Brown, R.J. Saykally, J. Phys. Chem. A 1997, 101, 8995; K. Liu, M.G. Brown, J.D. Cruzan, R.J. Saykally, J. Phys. Chem. A 1997, 101, 9011; J.D. Cruzan, M.R. Viant, M.G. Brown, R.J. Saykally, J. Phys. Chem. A 1997, 101, 9022; M.R. Viant, J.D. Cruzan, D.D. Lucas, M.G. Brown, and others, J. Phys. Chem. A 1997, 101, 9032. $^{b}$ M.G. Brown, F.N. Keutsch, R.J. Saykally, J. Chem. Phys. 1998 109, 9645.Author Institution: Department of Chemistry, University of California BerkeleyTerahertz VRT-spectra of small water clusters show splittings of the energy levels that can be explained by large amplitude vibrations and hydrogen bond rearrangement $dynamics^{a}$. For example, the cyclic water pentamer has an asymmetric equilibrium structure, and the effects of both the facile torsional motion of the free hydrogens (flipping) and the exchange of the free and bound hydrogen on one water molecule (bifurcation tunneling motion) are observed in the VRT $spectra^{b}$. In contrast, the cyclic water tetramer has an oblate symmetric top equilibrium structure before vibrational $averaging^{a}$. Whereas the flipping of one free hydrogen leads to a very large tunneling splitting in the water trimer and pentamer, there is no such facile process for the water tetramer. The high symmetry of the water tetramer requires a higher degree of cooperativity, which results in a far smaller number of facile tunneling motions. Although previous spectra and theoretical results indicate a tunneling process involving all four free hydrogens, the pathway is still unknown. A recently measured vibrational band at 4 THz allows us to gain new insight into the possible significant pathways

Fully coupled six-dimensional calculations of the water dimer vibration-rotation-tunneling states with a split Wigner pseudo spectral approach

A novel and efficient pseudospectral method for performing fully coupled six-dimensional bound state dynamics calculations is presented, including overall rotational effects. A Lanczos based iterative diagonalization scheme produces the energy levels in increasing energies. This scheme, which requires repetitively acting the Hamiltonian operator on a vector, circumvents the problem of constructing the full matrix. This permits the use of ultralarge molecular basis sets (up to over one million states for a given symmetry) in order to fully converge the calculations. The Lanczos scheme was conducted in a symmetry adapted spectral representation, containing Wigner functions attached to each monomer. The Hamiltonian operator has been split into different terms, each corresponding to an associated diagonal or nearly diagonal representation. The potential term is evaluated by a pseudospectral scheme of Gaussian accuracy, which guarantees the variational principle. Spectroscopic properties are computed with this method for four of the most widely used water dimer potentials, and compared against recent terahertz laser spectroscopy results. Comparisons are also made with results from other dynamics methods, including quantum Monte Carlo (QMC) and reversed adiabatic approximation calculations. None of the potential surfaces produces an acceptable agreement with experiments. While QMC methods yield good results for ground (nodeless) states, they are highly inaccurate for excited states