Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma.

Cell surface expression levels of GPRC5D, an orphan G protein-coupled receptor, are significantly higher on multiple myeloma (MM) cells, compared with normal plasma cells or other immune cells, which renders it a promising target for immunotherapeutic strategies. The novel GPRC5D-targeting T-cell redirecting bispecific antibody, talquetamab, effectively kills GPRC5D+ MM cell lines in the presence of T cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in bone marrow (BM) samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with bone marrow stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated lysis of primary MM cells in an additive fashion. In conclusion, we show that the GPRC5D-targeting T-cell redirecting bispecific antibody talquetamab is a promising novel antimyeloma agent. These results provide the preclinical rationale for ongoing studies with talquetamab in relapsed/refractory MM

Potent preclinical efficacy of DuoHexaBody-CD37 in B-cell malignancies

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A Rational Strategy for Reducing On-Target Off-Tumor Effects of CD38-Chimeric Antigen Receptors by Affinity Optimization

Chimeric antigen receptors (CARs) can effectively redirect cytotoxic T cells toward highly expressed surface antigens on tumor cells. The low expression of several tumor-associated antigens (TAAs) on normal tissues, however, hinders their safe targeting by CAR T cells due to on-target/off-tumor effects. Using the multiple myeloma (MM)-associated CD38 antigen as a model system, here, we present a rational approach for effective and tumor-selective targeting of such TAAs. Using “light-chain exchange” technology, we combined the heavy chains of two high-affinity CD38 antibodies with 176 germline light chains and generated ∼124 new antibodies with 10- to >1,000-fold lower affinities to CD38. After categorizing them into three distinct affinity classes, we incorporated the single-chain variable fragments of eight antibodies from each class into new CARs. T cells carrying these CD38-CARs were extensively evaluated for their on-tumor/off-tumor cytotoxicity as well as CD38-dependent proliferation and cytokine production. We identified CD38-CAR T cells of ∼1,000- fold reduced affinity, which optimally proliferated, produced Th1-like cytokines, and effectively lysed CD382+ MM cells, but spared CD38+ healthy hematopoietic cells in vitro and in vivo. Thus, this systematic approach is highly suitable for the generation of optimal CARs for effective and selective targeting of TAAs

Cognition, culture and utility:Plant classification by Paraguayan immigrant farmers in Misiones, Argentina

Background: This study was conducted in three rural communities of small farmers of Paraguayan origin living in the province of Misiones, Argentina. These Criollos (Mestizos) hail chiefly from departments located in the east of Paraguay, where the climate and flora have similar characteristics as those in Misiones. These ecological features contribute to the continuation and maintenance of knowledge and practices related to the use of plants. Methods: Fieldwork was conducted between September 2014 and August 2015. Forty five informants from three rural localities situated along the Parana River participated in an ethno-classification task. For the classification event, photographs of 30 medicinal and edible plants were chosen, specifically those yielding the highest frequency of mention among the members of that community (based on data obtained in the first stage of research in 2014). Variation in local plant classifications was examined and compared using principal component analysis and cluster analysis. Results: We found that people classify plants according to application or use (primarily medicinal, to a lesser extent as edible). Morphology is rarely taken into account, even for very similar and closely-related species such as varieties of palms. In light of our findings, we highlight a dominant functionality model at work in the process of plant cognition and classification among farmers of Paraguayan origin. Salient cultural beliefs and practices associated with rural Paraguayan plant-based medicine are described. Additionally, the manner by which residents’ concepts of plants articulate with local folk epistemology is discussed. Conclusions: Culturally constructed use patterns ultimately override morphological variables in rural Paraguayans’ ethnobotanical classification.Antecedentes: Este trabajo se realizó con pequeños agricultores de origen paraguayo, que habitan en la provincia de Misiones, Argentina. Los criollos (mestizos) en su mayoría provienen de departamentos ubicados al oriente del Paraguay, donde el clima y la flora presentan características similares a la provincia de Misiones. Estas características ecológicas contribuyen a la continuación y el mantenimiento de los conocimientos y las prácticas relacionados al uso de las plantas. Métodos El trabajo de campo se realizó entre septiembre de 2014 y agosto de 2015. En la etnoclasificación participaron 45 informantes, provenientes de tres localidades rurales, situadas a lo largo del río Paraná, frontera entre los dos países. Para la clasificación se utilizaron imágenes fotográficas de 30 especies -comestibles y medicinales- preseleccionadas como las de mayor frecuencia de mención entre los habitantes de la región (a partir de los datos obtenidos en una primera etapa de investigación en el año 2014). Por medio del análisis de componentes principales y el análisis de agrupamiento (cluster) se contrastaron y compararon las variaciones en las etnoclasificaciones locales de plantas. Resultados Se encontró que los pobladores clasifican sus plantas según su aplicación y uso (mayormente asociadas a la categoría medicinal y en menor medida a la comestible). Mientras, la morfología rara vez se tiene en cuenta, incluso en aquellas especies muy similares y estrechamente relacionadas como las palmeras. A la luz de los hallazgos, se destaca un modelo de funcionalidad dominante en el proceso de cognición y de clasificación de las plantas entre los agricultores de origen paraguayo. Se describen las principales creencias y prácticas culturales asociadas a la medicina rural paraguaya. Adicionalmente, se discuten algunos de los conceptos de las plantas que mantienen los paraguayos y su articulación con la epistemología local. Conclusiones En la clasificación etnobotánica de los pobladores de origen paraguayo los patrones de uso construidos culturalmente tienen mayor peso que las variables morfológicas.Fil: Kujawska, Monika. University Of Lodz; ArgentinaFil: Jiménez Escobar, Néstor David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Antropología de Córdoba. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Instituto de Antropología de Córdoba; ArgentinaFil: Nolan, Justin M.. University Of Arkansas; Estados UnidosFil: Arias Mutis, Daniel. University of Groningen; Países Bajo

Innovative Capability of Building Information Modeling in Construction Design

The construction industry has long been urged to innovate, but innovation has been elusive because of the inherent social and organizational complexity of construction. Therefore, developing insight into the practice of innovating is needed to better understand and perform innovation in construction. Focusing on the practice of innovating requires exploring the enabling capability of solutions for practitioners to establish novel ways of doing things for improvement, referred to as ‘innovative capability.’ Building information modeling (BIM) has been promoted as an enabler of innovation in construction design because of its data management capabilities and the opportunities for interdisciplinary work based on them. Nevertheless, previous work presents divergent results exploring what BIM technologies can do for people and what people can actually do in BIM-enabled design practices, which presents confusion about the innovative capability of BIM. This paper aims to establish the basis of this confusion as a necessary step in developing more realistic ways of assessing and exploiting this capability. A conceptual continuum is proposed based on the functionalist/technology-centered and nonfunctionalist/human-centered perspectives on BIM to consider divergent arguments about its innovative capability; this continuum is used to analyze empirical findings from BIM-enabled design practices. The analyses suggest that individuals use BIM but are confused about its innovative capability because they adopt different views of BIM depending on their job and perspective. Given this, innovation is held back by the unexpressed differences between the views of BIM adopted by various practitioners who have to work together. It is argued that recognizing these differences, and working toward their reconciliation, is the way forward in establishing and exploiting the innovative capability of BIM

Characterization of Protective Human CD4+CD25+ FOXP3+ Regulatory T Cells Generated with IL-2, TGF-β and Retinoic Acid

BACKGROUND: Protective CD4+CD25+ regulatory T cells bearing the Forkhead Foxp3 transcription factor can now be divided into three subsets: Endogenous thymus-derived cells, those induced in the periphery, and another subset induced ex-vivo with pharmacological amounts of IL-2 and TGF-β. Unfortunately, endogenous CD4+CD25+ regulatory T cells are unstable and can be converted to effector cells by pro-inflammatory cytokines. Although protective Foxp3+CD4+CD25+ cells resistant to proinflammatory cytokines have been generated in mice, in humans this result has been elusive. Our objective, therefore, was to induce human naïve CD4+ cells to become stable, functional CD25+ Foxp3+ regulatory cells that were also resistant to the inhibitory effects of proinflammatory cytokines. METHODOLOGY/PRINCIPAL FINDINGS: The addition of the vitamin A metabolite, all-trans retinoic acid (atRA) to human naïve CD4+ cells suboptimally activated with IL-2 and TGF-β enhanced and stabilized FOXP3 expression, and accelerated their maturation to protective regulatory T cells. AtRA, by itself, accelerated conversion of naïve to mature cells but did not induce FOXP3 or suppressive activity. The combination of atRA and TGF-β enabled CD4+CD45RA+ cells to express a phenotype and trafficking receptors similar to natural Tregs. AtRA/TGF-β-induced CD4+ regs were anergic and low producers of IL-2. They had potent in vitro suppressive activity and protected immunodeficient mice from a human-anti-mouse GVHD as well as expanded endogenous Tregs. However, treatment of endogenous Tregs with IL-1β and IL-6 decreased FOXP3 expression and diminished their protective effects in vivo while atRA-induced iTregs were resistant to these inhibitory effects. CONCLUSIONS/SIGNIFICANCE: We have developed a methodology that induces human CD4(+) cells to rapidly become stable, fully functional suppressor cells that are also resistant to proinflammatory cytokines. This methodology offers a practical novel strategy to treat human autoimmune diseases and prevent allograft rejection without the use of agents that kill cells or interfere with signaling pathways