Purpose: Urelumab is an agonist antibody to CD137 with potential application as an immuno-oncology therapeutic. Data were analyzed to assess safety, tolerability, and pharmacodynamic activity of urelumab, including the dose selected for ongoing development in patients with advanced solid tumors and lymphoma. Experimental Design: A total of 346 patients with advanced cancers who had progressed after standard treatment received at least one dose of urelumab in one of three dose–escalation, monotherapy studies. Urelumab was administered at doses ranging from 0.1 to 15 mg/kg. Safety analyses included treatment-related and serious adverse events (AEs), as well as treatment-related AEs leading to discontinuation and death, with a focus on liver function test abnormalities and hepatic AEs. Results: Urelumab doses between 1 and 15 mg/kg given every 3 weeks resulted in a higher frequency of treatment-related AEs than 0.1 or 0.3 mg/kg every 3 weeks. Dose was the single most important factor contributing to transaminitis development, which was more frequent and severe at doses ≥1 mg/kg. At the MTD of 0.1 mg/kg every 3 weeks, urelumab was relatively well tolerated, with fatigue (16%) and nausea (13%) being the most common treatment-related AEs, and was associated with immunologic and pharmacodynamic activity demonstrated by the induction of IFN-inducible genes and cytokines. Conclusions: Integrated evaluation of urelumab safety data showed significant transaminitis was strongly associated with doses of ≥1 mg/kg. However, urelumab 0.1 mg/kg every 3 weeks was demonstrated to be safe, with pharmacodynamic activity supporting continued clinical evaluation of this dose as monotherapy and in combination with other immuno-oncology agents. Clin Cancer Res; 23(8); 1929–36. ©2016 AACR.

Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody

Tuberculous meningitis (TBM) is the most severe complication of tuberculosis (TB) and is associated with high rates of disability and mortality. Mycobacterium tuberculosis (M. tb), the infectious agent of TB, disseminates from the respiratory epithelium, breaks through the blood-brain barrier, and establishes a primary infection in the meninges. Microglia are the core of the immune network in the central nervous system (CNS) and interact with glial cells and neurons to fight against harmful pathogens and maintain homeostasis in the brain through pleiotropic functions. However, M. tb directly infects microglia and resides in them as the primary host for bacillus infections. Largely, microglial activation slows disease progression. The non-productive inflammatory response that initiates the secretion of pro-inflammatory cytokines and chemokines may be neurotoxic and aggravate tissue injuries based on damages caused by M. tb. Host-directed therapy (HDT) is an emerging strategy for modulating host immune responses against diverse diseases. Recent studies have shown that HDT can control neuroinflammation in TBM and act as an adjunct therapy to antibiotic treatment. In this review, we discuss the diverse roles of microglia in TBM and potential host-directed TB therapies that target microglia to treat TBM. We also discuss the limitations of applying each HDT and suggest a course of action for the near future.

Potential of Neuroinflammation-Modulating Strategies in Tuberculous Meningitis: Targeting Microglia.

Exopolysaccharide (EPS-09) from L. plantarum WLPL09 was systemically investigated for the antitumor effect in B16F10 melanoma bearing mice model. The results showed that administraion of EPS-09 (200 mg/kg) could sigificantly inhibit the tumor growth of melanoma bearing mice, with a inhibition rate of 42.53 %. Meanwhile, compared to the Model group, high dose of EPS-09 (200 mg/kg) administraion could increase the spleen index (P = 0.10), promote the splenic lymphocytes proliferation under the stimulation of ConA and LPS with a proliferation rate of 120.58 % and 169.88 %, respectively, enhance the amount of CD4+ and CD8+ T cells (P < 0.0001, P = 0.0149) in tumor tissue, as well as the serum content of cytokines, i.e., TNF-α, IFN-γ, IL-2 (P < 0.05) and IL-6 (P = 0.039) of B16F10 melanoma bearing mice. The transcriptional level analysis revealed that EPS-09 (200 mg/kg) administraion could sigificantly (P < 0.05) upregulate the transcription of apoptosis raleted genes, i.e., P53, Caspase-3 and Caspase-9, and the ratio of Bax/Bcl-2, downregulate the transcription of angiogenesis markers, i.e., Vegf and Fgf2 compared with Model group. Furthermore, administration of EPS-09 could increase the abundance of phylum Firmicutes, family Ruminococcaceae and Lachnospiraceae, and genus Ruminococcus, but reduce the abundance of genus Prevotella, Akkermansia and Oscillospira. Taken together, these results indicate that administration of EPS-09 can induce apoptosis of tumor cell, inhibit tumor angiogenesis, improve the immunity, regulate the intestinal microbiota composition of B16F10 melanoma bearing mice, and play positive roles in the antitumor activity against melanoma. 

Antitumor effect of exopolysaccharide from Lactiplantibacillus plantarum WLPL09 on melanoma mice via regulating immunity and gut microbiota.

Vaccine targeting TNF epitope 1-14 do not suppress host defense against Mycobacterium bovis Bacillus Calmette-Guérin infection.

Background The commercial success of monoclonal antibodies (Mabs) has made biological therapeutics attractive to pharmaceutical companies. The priority of biopharmaceutical companies is to acquire and develop cell lines that enable them to manufacture biologics quickly, consistently, and economically. Clone selection is a critical process for cell line development. However, the traditional clone selection process requires the evaluation of large numbers of clones using cell growth rate, cell densities and titer, product quality, and so on. Methods To improve efficiency of the clone selection strategies, we developed a relative titer (RT) prediction model by the quantitative information extracted from microscope images during the cell line development process. The performance of this RT prediction model was further evaluated with 50 clones from 5 different cell lines. Results The RT prediction model was able to predict high producers from a given data set when the same host cells were used. Although inaccurate prediction occurred when different host cell was used, this RT prediction model may serve as an excellent proof of concept study that quantitative information from cell line development images provides valuable information to facilitate the cell line development process. Conclusions Here, we present the first predictive model that can be used to estimate the relative productivity of Chinese hamster ovaries (CHO) clones during the cell line development. Additional experiments are currently in process to further improve the RT predictive model. Nevertheless, our current study will serve as a foundation for more prediction models for cell line development that can facilitate the selection of clones.

/pdf/selection-of-high-producing-clones-by-a-relative-titer-5d49677jqs.pdf

Selection of high-producing clones by a relative titer predictive model using image analysis.

https://www.mdpi.com/2076-393X/8/2/223/pdf

Recombinant Costimulatory Fusion Proteins as Functional Immunomodulators Enhance Antitumor Activity in Murine B16F10 Melanoma

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Vaccine targeting TNF epitope 1-14 do not suppress host defense against Mycobacterium bovis Bacillus Calmette-Guérin infection.

Selection of high-producing clones by a relative titer predictive model using image analysis.

Recombinant Costimulatory Fusion Proteins as Functional Immunomodulators Enhance Antitumor Activity in Murine B16F10 Melanoma