An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif.

Triglycerides (TG) are required for fatty acid transport and storage and are essential for human health. Angiopoietin-like-protein 8 (ANGPTL8) has previously been shown to form a complex with ANGPTL3 that increases circulating TG by potently inhibiting LPL. We also recently showed that the TG-lowering apolipoprotein A5 (ApoA5) decreases TG levels by suppressing ANGPTL3/8-mediated LPL inhibition. To understand how LPL binds ANGPTL3/8 and ApoA5 blocks this interaction, we used hydrogen-deuterium exchange mass-spectrometry and molecular modeling to map binding sites of LPL and ApoA5 on ANGPTL3/8. Remarkably, we found that LPL and ApoA5 both bound a unique ANGPTL3/8 epitope consisting of N-terminal regions of ANGPTL3 and ANGPTL8 that are unmasked upon formation of the ANGPTL3/8 complex. We further used ANGPTL3/8 as an immunogen to develop an antibody targeting this same epitope. After refocusing on antibodies that bound ANGPTL3/8, as opposed to ANGPTL3 or ANGPTL8 alone, we utilized bio-layer interferometry to select an antibody exhibiting high-affinity binding to the desired epitope. We revealed an ANGPTL3/8 leucine zipper-like motif within the anti-ANGPTL3/8 epitope, the LPL-inhibitory region, and the ApoA5-interacting region, suggesting the mechanism by which ApoA5 lowers TG is via competition with LPL for the same ANGPTL3/8-binding site. Supporting this hypothesis, we demonstrate that the anti-ANGPTL3/8 antibody potently blocked ANGPTL3/8-mediated LPL inhibition in vitro and dramatically lowered TG levels in vivo. Together, these data show that an anti-ANGPTL3/8 antibody targeting the same leucine zipper-containing epitope recognized by LPL and ApoA5 markedly decreases TG by suppressing ANGPTL3/8-mediated LPL inhibition.

Generation and Characterization of Torudokimab (LY3375880): A Monoclonal Antibody That Neutralizes Interleukin-33.

BACKGROUND: Interleukin-33 (IL-33) is an alarmin that is released following cellular damage, mechanical injury, or necrosis. It is a member of the IL-1 family and binds to a heterodimer receptor consisting of ST2 and IL-1RAP to induce the production of a wide range of cellular mediators, including the type 2 cytokines IL-4, IL-5 and IL-13. This relationship has led to the hypothesis that the IL-33/ST2 pathway is a driver of allergic disease and inhibition of the IL-33 and ST2 association could have therapeutic benefit. METHODS: In this paper, we describe the selection of a phage antibody through the ability to bind human IL-33 and block IL-33/ST2 interaction. This hit antibody was then affinity matured by site-directed mutagenesis of the antibody complementarity-determining regions (CDRs). Further characterization of a fully human monoclonal antibody (mAb), torudokimab (LY3375880) included demonstration of human IL-33 neutralization activity in vitro with an NFκB reporter assay and IL-33 induced mast cell cytokine secretion assay, followed by an in vivo IL-33-induced pharmacodynamic inhibition assay in mice that used IL-5 production as the endpoint. RESULTS: Torudokimab is highly specific to IL-33 and does not bind any of the other IL-1 family members. Furthermore, torudokimab binds human and cynomolgus monkey IL-33 with higher affinity than the binding affinity of IL-33 to ST2, but does not bind mouse, rat, or rabbit IL-33. Torudokimab's half-life in cynomolgous monkey projects monthly dosing in the clinic. CONCLUSION: Due to torudokimab's high affinity, its ability to completely neutralize IL-33 activity in vitro and in vivo, and the observed cynomolgus monkey pharmacokinetic properties, this molecule was selected for clinical development.

Flipside of the Coin: Iron Deficiency and Colorectal Cancer.

Iron deficiency, with or without anemia, is the most frequent hematological manifestation in individuals with cancer, and is especially common in patients with colorectal cancer. Iron is a vital micronutrient that plays an essential role in many biological functions, in the context of which it has been found to be intimately linked to cancer biology. To date, however, whereas a large number of studies have comprehensively investigated and reviewed the effects of excess iron on cancer initiation and progression, potential interrelations of iron deficiency with cancer have been largely neglected and are not well-defined. Emerging evidence indicates that reduced iron intake and low systemic iron levels are associated with the pathogenesis of colorectal cancer, suggesting that optimal iron intake must be carefully balanced to avoid both iron deficiency and iron excess. Since iron is vital in the maintenance of immunological functions, insufficient iron availability may enhance oncogenicity by impairing immunosurveillance for neoplastic changes and potentially altering the tumor immune microenvironment. Data from clinical studies support these concepts, showing that iron deficiency is associated with inferior outcomes and reduced response to therapy in patients with colorectal cancer. Here, we elucidate cancer-related effects of iron deficiency, examine preclinical and clinical evidence of its role in tumorigenesis, cancer progression and treatment response. and highlight the importance of adequate iron supplementation to limit these outcomes.

New introducer PEG gastropexy does not require prophylactic antibiotics: multicenter prospective randomized double-blind placebo-controlled study.

BACKGROUND: Peristomal infections are the most common complications of PEG, despite prophylactic antibiotics. The "introducer" PEG-placement technique avoids the sojourn of a PEG catheter through the oropharynx, and hence minimizes the chances of infectious complications. Despite the obvious potential advantage, this technique failed to gain popularity, mainly as a result of other associated risks and complications. Recently, a modified introducer endoscopic PEG-gastropexy technique was shown to be quite safe. The present study is the first study that evaluated the need of prophylactic antibiotics for "introducer" PEG. OBJECTIVE: To determine the incidence of peristomal wound infections during the immediate 7-day postprocedure follow-up. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTINGS: Multicenter; a university tertiary-care hospital and a private practice endoscopy clinic. PATIENTS: A total of 633 patients undergoing PEG were assessed for inclusion. Ninety-seven patients who had malignant stenotic oropharyngeal stricture were randomized: group I (49 patients) received prophylactic ceftriaxone, and group II (48 patients) received a placebo. Both groups were similar in patient characteristics. INTERVENTIONS: Introducer PEG was performed by using the Freka Pexact-15 CH/FR, with the gastric wall nonsurgically sutured to the anterior abdominal wall by use of an endoscope. MAIN OUTCOME MEASUREMENTS: The peristomal area was assessed daily for 7 days by using 2 different types of infection scores. RESULTS: Clinically significant wound reaction was observed in 1 patient in each group. Wound infection scores were marginally higher in the placebo group, but the differences in the values of infection scores between both the groups were not statistically significant during the 7-day post-PEG follow-up. LIMITATIONS: The introducer gastropexy kit is 5 times more expensive than the "pull" PEG. CONCLUSIONS: The new introducer PEG-gastropexy technique can be performed safely, without prophylactic antibiotics in patients potentially at high risk of peristomal infectious complications (those with advanced oropharyngeal malignancy) (ClinicalTrials.gov identifier NCT00375414).

Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases.

Anemia is a common complication of inflammatory bowel diseases. An international working party has formed and developed guidelines for evaluation and treatment of anemia and iron deficiency that should serve practicing gastroenterologists. Within a total of 16 statements, recommendations are made regarding diagnostic measures to screen for iron- and other anemia-related deficiencies regarding the triggers for medical intervention, treatment goals, and appropriate therapies. Anemia is a common cause of hospitalization, prevents physicians from discharging hospitalized patients, and is one of the most frequent comorbid conditions in patients with inflammatory bowel disease. It therefore needs appropriate attention and specific care.