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Tumour antigen targeted antibodies (mAbs) can induce natural killer (NK) cells to kill tumours through antibody dependent cellular cytotoxicity (ADCC) upon engagement of NK cell expressed FcγRIIIa. FcγRIIIa polymorphisms partially dictate the potency of the ADCC response. The high affinity FcγRIIIa-158-valine (V) polymorphism is associated with more potent ADCC response than the low affinity FcγRIIIa-158-phenylalanine (F) polymorphism. Because approximately 45% of patients are homozygous for the FcγRIIIa-158-F polymorphism (FF genotype), their ability to mount ADCC is impaired. We investigated whether a novel mAb capable of binding multiple antigen specific targets and engaging multiple low affinity FcγRIIIa receptors could further enhance ADCC against colon cancer in vitro. Specifically, we generated a novel anti-epidermal growth factor receptor (EGFR) antibody (termed a stradobody) consisting of an unmodified Fab sequence and two Immunoglobulin G, subclass 1 (IgG1) Fc domains separated by an isoleucine zipper domain and the 12 amino-acid IgG2 hinge. The stradobody framework induced multimerisation and was associated with increased binding to the EGFR and FcγRIIIa. From a functional perspective, when compared to an unmodified anti-EGFR mAb with a sequence identical to cetuximab (a commercially available anti-EGFR mAb), stradobodies significantly enhanced ADCC. These effects were observed using both KRAS wild type HT29 and KRAS mutant SW480 colon cancer cells as targets, and by NK cells obtained from healthy donors and a cohort of patients with colon cancer. These data suggest that high avidity cross-linking of multiple tumour surface antigens and multiple NK cell associated FcγRIIIa molecules can enhance ADCC and partially overcome impaired ADCC by FF genotype individuals in vitro.

A 51-year-old woman with dermatomyositis (DM) on chronic immunosuppressive therapy was hospitalised for evaluation of haematuria. Surprisingly, abdominal imaging demonstrated pneumoperitoneum and pneumatosis intestinalis (PI). Her abdominal examination and white cell count were normal, but she subsequently developed nausea and fever. Owing to concern for perforation, a hemicolectomy was performed. Pathology revealed PI without inflammatory, ischaemic or neoplastic features, and she recovered uneventfully. Her immunosuppressive therapy was discontinued. Six months later, a follow-up CT of the abdomen revealed recurrence of PI. As she was asymptomatic, she was managed conservatively with resolution of PI on subsequent imaging. PI is characterised by the presence of gas within the wall of the intestine. Its aetiology is often unclear but this case highlights the association between PI and both immunosuppressive therapy and DM. A review of PI in patients with DM suggests that clinically stable patients may be observed, while avoiding surgical intervention.

Orlistat is a United States Food and Drug Administration (FDA)-approved drug indicated for the management of obesity. The FDA has issued a warning of rare, but severe, reports of liver injury after orlistat use. We describe a 40-year-old woman with no significant medical history who experienced fulminant liver failure after orlistat use. Two weeks after taking the drug at a low dosage of 60 mg/day for 4 days, she developed significant fatigue, nausea, right upper abdominal discomfort, and icterus, and her liver enzyme panel showed significant abnormalities. Five weeks later, after further deterioration in her clinical status, she was transferred to our medical center with severe cholestasis and coagulopathy Liver ultrasonography, serologies for viral hepatitis, and autoimmune markers were unremarkable. Early cessation of the drug was not sufficient to stop the progression of liver injury, and she required an orthotopic liver transplant. Two weeks after transplantation, she was discharged in good condition. Published reports of liver injury associated with orlistat use describe a presentation similar to that of our patient. Although use of the Naranjo adverse reaction probability scale indicated a possible relationship (score of 3) between the patient's development of fulminant liver failure and orlistat, we believe this was a drug-induced case and is consistent with previous reports. To our knowledge, this is the first published report of orlistat-induced liver failure in the United States. Although orlistat may be a useful drug for weight loss, clinicians should be aware that its use can rarely cause idiosyncratic hepatotoxicty characterized by subacute hepatitis, which may progress to serious injury.