Open Access

TNFR2 is an emerging therapeutic target in immuno-oncology. We have previously shown that an agonistic mouse TNFR2 antibody was able to activate CD8+ T cells in vitro and has anti-tumor activity in multiple syngeneic mouse tumor models. This activity required CD8+ T cell and NK cell response and involves Fc γ receptor engagement. Based on this compelling evidence, we have developed MM-401, a human antibody targeting the TNFR2 receptor. MM-401 was humanized from a mouse hybridoma antibody by CDR grafting and includes additional mutations for improved affinity and biophysical properties. Consequently, MM-401 binds with low nanomolar affinity to a region in human TNFR2 that corresponds to the mouse TNFR2 epitope of our mouse surrogate antibody. Although the antibody competes with TNF α in binding the receptor, MM-401 has agonistic activity and induces TNFR2 signaling as observed using a NFκB reporter cell assay. Upon incubation of MM-401 with CD4+ and CD8+ T cells from healthy human blood, we observed upregulation of activation markers and cytokine production comparable to utomilumab (anti-4-1BB), MEDI6469 (anti-OX40), and TRX518 (anti-GITR). We also observed that MM-401 promotes antibody-dependent cellular cytotoxicity (ADCC) in an NK cell-mediated in vitro assay and a reduction in the number regulatory T (Treg) cells in ovarian cancer ascites samples. These data suggest that MM-401 could also promote anti-tumor immunity by mediating ADCC, as well as by direct co-stimulation of T cell responses. Currently, we are evaluating MM-401 in patient derived xenograft (PDX) models in humanized mice generated using NSG-SGM3 mice with cord blood CD34+ hematopoietic stem cells. These results justify the continued development of MM-401 as a modulator of anti-tumor immunity for the treatment of cancer.

The data set includes a current representative management treatment from detailed, quality-tested sentinel field experiments with wheat from four contrasting environments including Australia, The Netherlands, India and Argentina. Measurements include local daily climate data (solar radiation, maximum and minimum temperature, precipitation, surface wind, dew point temperature, relative humidity, and vapor pressure), soil characteristics, frequent growth, nitrogen in crop and soil, crop and soil water and yield components. Simulations include results from 27 wheat models and a sensitivity analysis with 26 models and 30 years (1981-2010) for each location, for elevated atmospheric CO2 and temperature changes, a heat stress sensitivity analysis at anthesis, and a sensitivity analysis with soil and crop management variations and a Global Climate Model end-century scenario. Data access via DOI 10.17026/DANS-ZB6-6FVQ