The 5-HT2C receptor agonist lorcaserin (Belviq®) has been Food and Drug Administration (FDA) approved for the treatment of obesity. The present study is a back translational investigation into the effect of 28-day lorcaserin treatment in a diet-induced obesity (DIO) model using male, Sprague–Dawley rats. An assessment of drug effect on efficacy and multiple safety endpoints including cardiac function was undertaken. Lorcaserin (1–2 mg/kg SC b.i.d.) significantly reduced percentage body weight gain compared to vehicle-treated controls (VEH: 10.6 ± 0.4%; LOR 1: 7.6 ± 1.2%; LOR 2: 5.4 ± 0.6%). Measurement of body composition using quantitative magnetic resonance (QMR) imaging indicated this change was due to the selective reduction in body fat mass. Modest effects on food intake were recorded. At the completion of the treatment phase, echocardiography revealed no evidence for valvulopathy, that is, no aortic or mitral valve regurgitation. The pharmacokinetics of the present treatment regimen was determined over a 7-day treatment period; plasma Cmin and Cmax were in the range 13–160 ng/mL (1 mg/kg b.i.d.) and 34–264 ng/mL (2 mg/kg b.i.d.) with no evidence for drug accumulation. In sum, these studies show an effect of lorcaserin in the DIO model, that in the context of the primary endpoint measure of % body weight change was similar to that reported clinically (i.e., 3.0–5.2% vs. 3.2%). The present studies highlight the translational value of obesity models such as DIO, and suggest that assuming consideration is paid to nonspecific drug effects such as malaise, the DIO model has reasonable forward translational value to help predict clinical outcomes of a new chemical entity.

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Background In Inflammatory Bowel Disease (IBD), intestinal barrier dysfunction and epithelial cell injury are believed to be associated with activation of the immune system to drive disease-associated inflammation, which together constitute key features of active disease. Existing drugs used to treat IBD induce endoscopic remission and improvements in mucosal healing in only a minor proportion of patients, driving a critical need for therapies which lead directly to mucosal healing. Furthermore, predicting patients who may benefit from therapeutics that address specific mechanisms of mucosal healing may augment response rates. Methods We screened proteins, identified from a meta-analysis of healthy human microbiome, in cellular assays and animal models related to mucosal injury, with the goal of identifying novel therapeutics that have the potential to directly induce mucosal healing. The proteins identified were further optimized by protein engineering to increase their stability as well as gastro-intestinal (GI) targeting via oral administration. For this, therapeutic proteins were expressed using a probiotic, Lactococcus lactis (L.lactis), engineered to display the recombinant proteins on the cell surface, and evaluated for activity in DSS- and DNBS-induced models of colitis in mice. Mechanism of action studies using computational and laboratory based methods to analyze gene expression and direct molecular interactions with human proteins, enabled the identification of pathways modulated by the candidate molecules. These pathways were further evaluated for their ability to identify biomarkers in specific patients most suitable for treatment in a precision medicine approach. Results We have identified a novel, healthy microbiome-derived protein that demonstrated robust activity in human epithelial injury assays in vitro. The protein reduced intestinal injury related pathology in mice when orally administered to target directly the GI tract. SG-5-00455, the product based on an L.lactis strain expressing the candidate therapeutic protein, reduced pathology scores, inflammation and barrier function related LPS-binding protein levels to levels comparable to those obtained glucagon-like peptide 2 (GLP-2), as well as improving dysregulated tissue repair and fibrosis-associated gene expression and proteins levels. SG-5-0455 treatment did not result in systemic exposure, driving its therapeutic activity in a GI-localized manner by targeting pathways related to tissue injury and fibrinolysis. Conclusion SG-5-00455, through its novel mechanism of action and oral delivery to directly target tissue repair pathways in the GI-tract, offers the potential to address a large critical need in IBD.

The gut microbiota has emerged as an important player in cancer pathology, and increasing evidence supports its role in clinical response to immune checkpoint inhibitor (ICI) therapy. However, the specific microbiome-derived factors responsible for the improved response to ICI therapy remain unknown. Second Genome has developed a unique discovery platform to identify, screen, and validate microbiome-derived peptides that promote response to cancer immunotherapy. Using our multitechnology meta-analysis of published datasets and characterizing the baseline microbiome of melanoma patients treated with anti-PD-1, we have identified gut microbiome strains differentially abundant in responders versus nonresponders that are concordant across multiple cohorts. Next, peptides from strains associated with responder signatures were predicted from their genome sequences. In addition, we predicted peptides from assembled metagenomes that were associated with responders. The predicted peptides were screened using phage display technology to identify binders to immune cells known to play a role in the tumor microenvironment (TME). Peptides that bound to specific immune cells were then evaluated for activity in cell-based assays using isolated primary human T cells, dendritic cells (DCs), and macrophages. We have demonstrated that several microbiome-derived peptides induce secretion of proinflammatory cytokines and chemokines such as CXCL10 and TNF-α by primary human monocyte-derived dendritic cells (moDCs), as well as secretion of effector cytokines such as IFNγ and IL-2 by primary human T cells. We have also identified microbiome-derived peptides with the capacity to inhibit an M2-like phenotype in macrophages (decreased LPS-induced IL-10 secretion). These effects were dose dependent and evident across immune cells derived from multiple human blood donors. In a coculture assay using allogeneic moDCs and T cells from human donors, combination of our DC-activating peptides with CD40 agonistic antibody and/or anti-PD-L1 induced secretion of proinflammatory cytokines such as IFNγ and TNF-α. In vivo, peritumoral administration of a candidate DC-activating peptide into RENCA tumor-bearing mice led to a significant reduction in tumor volume as compared to the control-treated mice. Collectively, these data demonstrate the potential of the microbiome-derived peptides identified by Second Genome’s discovery platform to modulate immune-cell effector functions in vitro and promote antitumor immunity in vivo. These results validate the unique approach of Second Genome’s discovery platform to identify novel microbiome-derived agents with potential for use as therapeutics in cancer immunotherapy. This abstract is also being presented as Poster B19. Citation Format: Dhwani D. Haria, Jayamary Divya Ravichandar, Lynn Yamamoto, Bernat Baeza-Raja, Ashil Bans, Cheryl-Emiliane Chow, Jill Desnoyer, Joanna Dreux, Shoko Iwai, Sabina Lau, Jina Lee, Michelle Lin, Paul Loriaux, Nicole Narayan, Eskedar Nigatu, Erica Rutherford, Michi Wilcoxon, Yonggan Wu, Todd DeSantis, Toshihiko Takeuchi, Karim Dabbagh, Helena Kiefel. Novel microbiome-derived peptides modulate immune cell activity and the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr PR08.

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