The rockefeller university

Chemically programmed bispecific antibodies (biAbs) endow target cell-binding small molecules with the ability to recruit and activate effector cells of the immune system. Here we report a platform of chemically programmed biAbs aimed at redirecting cytotoxic T cells to eliminate cancer cells. Two different antibody technologies were merged together to make a novel chemically programmed biAb. This was achieved by combining the humanized anti-hapten monoclonal antibody (mAb) h38C2 with the humanized anti-human CD3 mAb v9 in a clinically investigated diabody format known as Dual-Affinity Re-Targeting (DART). We show that h38C2 x v9 DARTs can readily be equipped with tumor-targeting hapten-derivatized small molecules without causing a systemic response harming healthy tissues. As a proof of concept, we chemically programmed h38C2 x v9 with hapten-folate and demonstrated its selectivity and potency against folate receptor 1 (FOLR1)-expressing ovarian cancer cells in vitro and in vivo. Unlike conventional biAbs, chemically programmed biAbs in DART format are highly modular with broad utility in terms of both target and effector cell engagement. Most importantly, they provide tumor-targeting compounds access to the power of cancer immunotherapy.

The developmental transcription factor SOX4 contributes to the metastatic spread of multiple solid cancer types, but its direct target genes that mediate cancer progression are not well defined. Using a systematic molecular and genomic approach, we identified the TMEM2 transmembrane protein gene as a direct transcriptional target of SOX4. TMEM2 was transcriptionally activated by SOX4 in breast cancer cells where, likeSOX4, TMEM2 was found to mediate proinvasive and promigratory effects. Similarly, TMEM2 was sufficient to promote metastatic colonization of breast cancer cells and its expression in primary breast tumors associated with a higher likelihood of metastatic relapse. Given earlier evidence that genetic inactivation of SOX4 or TMEM2 yield similar defects in cardiac development, our findings lead us to propose that TMEM2 may not only mediate the pathologic effects of SOX4 on cancer progression but also potentially its contributions to embryonic development. (C) 2016 AACR.

In this paper, we generalize the theory of Brownian motion and the Onsager-Machlup theory of fluctuations for spatially symmetric systems to equilibrium and nonequilibrium steady-state systems with a preferred spatial direction, due to an external force. To do this, we extend the Langevin equation to include a bias, which is introduced by an external force and alters the Gaussian structure of the system's fluctuations. In addition, by solving this extended equation, we provide a physical interpretation for the statistical properties of the fluctuations in these systems. Connections of the extended Langevin equation with the theory of active Brownian motion are discussed as well.

A vaccine that elicits broadly neutralizing antibodies (bNAbs) against HIV-1 is likely to be protective, but this has not been achieved. To explore immunization regimens that might elicit bNAbs, we produced and immunized mice expressing the predicted germline PGT121, a bNAb specific for the V3-loop and surrounding glycans on the HIV-1 spike. Priming with an epitope-modified immunogen designed to activate germline antibody-expressing B cells, followed by ELISA-guided boosting with a sequence of directional immunogens, native-like trimers with decreasing epitope modification, elicited heterologous tier-2-neutralizing responses. In contrast, repeated immunization with the priming immunogen did not. Antibody cloning confirmed elicitation of high levels of somatic mutation and tier-2-neutralizing antibodies resembling the authentic human bNAb. Our data establish that sequential immunization with specifically designed immunogens can induce high levels of somatic mutation and shepherd antibody maturation to produce bNAbs from their inferred germline precursors.

Targeting the signaling pathway of the immunosuppressive metabolite adenosine is an emerging approach for cancer immunotherapy. In this issue of Cancer Cell, Young et al. describe that co-inhibition of the adenosingenic pathway through blockade of both CD73 and A2AR enhances antitumor efficacy through distinct mechanisms.

In Texas, Arizona, and New Mexico, colonias refer to unincorporated rural settlements along the U.S. Mexico border. Colonias lack governance and public services normally provided by local government (Ward, 1999). Residents typically rely on well water or hauled water stored in above-ground containers. This study attempted to quantify and compare water-related perceptions and practices of colonia residents. No significant differences were observed between colonia residents using well water versus hauled-stored water for water quality perceptions and water use practices. Most, however, had negative perceptions of their water supply; a majority perceived daily water supplies as not potable. Significant paradoxical discrepancies between perceptions and practice were identified. This study adds to a small but growing literature on subjective dimensions of quality of life indicators for colonia residents. Additional studies are needed to quantify the type and level of health risks posed by compromised water supplies for this vulnerable population. Understanding differences in perceptions and practices associated with water sources could help to identify which subpopulations of colonia residents are in greatest need of water infrastructure or remediation.

The parasitic protozoa Trypanosome brucei and Plasmodium falciparum are lethal human parasites that have developed elegant strategies of immune evasion by antigenic variation. Despite the vast evolutionary distance between the two taxa, both parasites employ strict monoallelic expression of their membrane proteins, variant surface glycoproteins in Trypanosomes and the var, rif and stevor genes in Plasmodium, in order to evade their host's immune system. Additionally, both telomeric location and epigenetic controls are prominent features of these membrane proteins. As such, telomeres, chromatin structure and nuclear organization all contribute to control of gene expression and immune evasion. Here, we discuss the importance of epigenetics and sub-nuclear context for the survival of these disease-causing parasites. (C) 2016 Elsevier B.V. All rights reserved.

Germinal centers (GCs) are the site of antibody diversification and affinity maturation and as such are vitally important for humoral immunity. The study of GC biology has undergone a renaissance in the past 10 years, with a succession of findings that have transformed our understanding of the cellular dynamics of affinity maturation. In this review, we discuss recent developments in the field, with special emphasis on how GC cellular and clonal dynamics shape antibody affinity and diversity during the immune response.