Engineered antibody Fc variants with enhanced effector function

Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fcgamma receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fcgamma receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.     

Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor

BI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3′-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC₅₀s) of <15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of >90 μM. BI 224436 also has a low, ∼2.1-fold decrease in antiviral potency in the presence of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits serum-shifted EC₉₅ values ranging between 22 and 75 nM. Passage of virus in the presence of inhibitor selected for either A128T, A128N, or L102F primary resistance substitutions, all mapping to a conserved allosteric pocket on the catalytic core of integrase. BI 224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials.     

Validity of conventional surgical treatment methods for mandibular dentigerous cysts. Two case reports

Dentigerous cysts, which are the most commonly seen odontogenic cysts in the jaws, usually expand asymptomatically and extensively. They are surgically eliminated along with the accompanying impacted tooth, because of their destructive nature to the surrounding vital structures, tissues, bone and teeth. The surgical treatment for removing dentigerous cysts includes decompression, marsupialization, enucleation or curettage of the cyst through an extraoral or intraoral approach. Cysts causing tooth displacement and involving loss of bone are treated by marsupialization or decompression, followed by enucleation. In the cases presented here, both patients had enlarged dentigerous cysts in the left mandibular molar region, with an accompanying impacted tooth. Both cases were treated surgically by the enucleation technique alone, without any need for additional autogenous grafts or alloplastic materials to regain integrity of bone structure. They were rehabilitated with dental implants. The implant-retained fixed prostheses functioned well throughout the 24-month evaluation time; and the functional and psychological needs of the patients were provided successfully.     

The effect of unilateral forced nostril breathing on sleep in healthy right-handed men: a preliminary report

Purpose

Although we spend about one-third of our lives in sleep and recognize its necessity for good health, sleep has only been partially elucidated in the last century. The nasal cycle of congestion and decongestion during sleep has various effects on human physiology. The aim of the present study was to investigate the effect of unilateral forced nostril breathing on sleep.

Methods

Twenty-one healthy male volunteers aged 18–24 years were included in the study. Only individuals with right-hand dominance were included. Subjects were observed during sleep for three nights under different conditions: no obstruction (normal sleep) on the first night, right nasal obstruction on the second night, and left nasal obstruction on the third night.

Results

The main findings of our study are that sleep efficiency, NREM stage III, and total sleep duration were greater during left nasal obstruction (right nostril dominant respiration), while apnea-hypopnea index (AHI), frequency of periodic limb movements, and oxygen desaturation were higher during right nasal obstruction (left nostril dominant respiration).

Conclusion

The nasal cycle has a significant impact on sleep which is reflected in sleep recordings. Our result supports that nasal obstructions, due to deviations, concha hypertrophy, or congestion/decongestion, might affect the physiology of respiration and sleep. Nasal obstruction should be taken into consideration when evaluating patients in sleep laboratories and further studies are required to elucidate the situation in the patients with nasal obstruction.

     

CMV retinitis after intravitreal triamcinolone acetonide injection in a patient with Behçet’s uveitis

We report the case of a patient with Behçet’s uveitis who developed cytomegalovirus (CMV) retinitis after intravitreal triamcinolone acetonide (IVTA) injection. We reviewed the patient’s chart for the purpose of this report. An IVTA injection was performed for treatment of severe panuveitis in the left eye of a 30-year-old male patient with Behçet’s disease. Systemic treatment included high dose corticosteroid and azathioprine. Fourteen weeks after IVTA, extensive areas of necrotizing retinitis developed in the left eye. Polymerase chain reaction of serum and vitreous samples was positive for CMV DNA. Serum anti-CMV IgG was positive, IgM was negative, anti-HIV antibody was negative, complete blood count was normal, and CD4 count was 1,060 cells/μl. The patient responded well to intravitreal ganciclovir injection performed twice and intravenous ganciclovir treatment administered for five weeks. Local immunosuppression with IVTA may cause CMV retinitis. Awareness of this serious complication is important for correct diagnosis and treatment.