IntroductionCD40 ligand (CD40L) blockade has demonstrated efficacy in experimental autoimmune models. However, clinical trials of hu5c8, an anti-human CD40L IgG1 antibody, in systemic lupus erythematosus (SLE) were halted due to an increased incidence of thrombotic events. This study evaluated CDP7657, a high affinity PEGylated monovalent Fab' anti-CD40L antibody fragment, to assess whether an Fc-deficient molecule retains efficacy while avoiding the increased risk of thrombotic events observed with hu5c8.MethodsThe potency and cross-reactivity of CDP7657 was assessed in in vitro assays employing human and non-human primate leukocytes, and the capacity of different antibody formats to activate platelets in vitro was assessed using aggregometry and dense granule release assays. Given the important role CD40L plays in regulating humoral immunity, in vivo efficacy was assessed by investigating the capacity of Cynomolgus monkeys to generate immune responses to the tetanus toxoid antigen while the potential to induce thrombotic events in vivo was evaluated after repeat dosing of antibodies to Rhesus monkeys. A PEGylated anti-mouse CD40L was generated to assess efficacy in the New Zealand Black/White (NZB/W) mouse model of SLE.ResultsCDP7657 dose-dependently inhibited antigen-specific immune responses to tetanus toxoid in Cynomolgus monkeys, and in contrast to hu5c8, there was no evidence of pulmonary thrombovasculopathy in Rhesus monkeys. Aglycosyl hu5c8, which lacks Fc receptor binding function, also failed to induce thrombotic events in Rhesus monkeys. In vitro experiments confirmed that antibody constructs lacking an Fc, including CDP7657, did not induce human or monkey platelet activation. A PEGylated monovalent Fab' anti-mouse CD40L antibody also inhibited disease activity in the NZB/W mouse model of SLE after administration using a therapeutic dosing regimen where mice received antibodies only after they had displayed severe proteinuria.ConclusionsThese findings demonstrate for the first time that anti-CD40L antibodies lacking a functional Fc region do not induce thrombotic events in Rhesus monkeys and fail to activate platelets in vitro but, nevertheless retain pharmacological activity and support the investigation of CDP7657 as a potential therapy for systemic lupus erythematosus and other autoimmune diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0757-4) contains supplementary material, which is available to authorized users.

SummaryOtorhinolaryngology, a product of the early 20th century, developed from the joining together of the separate departments of otology, whose practitioners were surgeons, and laryngology which was managed by physicians who also treated diseases of the nose and chest. The 20th century opened with brave attempts to perform skilful surgery under conditions of primitive anaesthesia and no antibiotics. The stimulus of two world wars led to significant advances in technology and greater opportunities to explore new and resurrect old surgical procedures. The discovery of antibiotics saw an end to acute mastoiditis and the complications of otitis media and sinusitis, as well as a decline in the number of tonsillectomy and adenoidectomy operations.Over the last 30 years the specialty has undergone dramatic development and has taken advantage of new advances in endoscopy, microsurgery, the use of lasers, cytotoxic drugs, flap reconstruction and microchip technology. During the same period, although still calling themselves otorinolaryngologists, individual surgeons have subspecialised in otology, otoneurosurgery and skull-base surgery, head and neck surgery, phonosurgery, rhinology and facioplastic surgery, and paediatric otothinolaryngology. Each of these subspecialties has its own societies and specialist journals. Keywords: otorhinolaryngology; history of medicineThe specialty of otorhinolaryngology (or ear, nose and throat surgery (ENT)) is a product of the early 20th century, for it was then that the separate fields of otology and laryngology were joined together. Otologists were surgeons while laryngologists were physicians who also treated diseases of the nose and chest.During the first half of the 18th century the great advances in anatomical knowledge of the area, combined with an early understanding of its physiology and pathology, were not matched by advances in treatment which was entirely empirical. Eustachian tube catheterisation (1724), myringotomy or piercing of the ear drum (1801) and early attempts at mastoidectomy (1774) were to remain the main surgical treatments until the middle of the 19th century when anaesthetics and antisepsis were introduced.

Antibody-targeted chemotherapy with immunoconjugates of calicheamicin is a clinically validated strategy in cancer therapy. This study describes the selection of a murine anti-CD22 mAb, m5/44, as a targeting agent, its conjugation to a derivative of calicheamicin (CalichDM) via either acid-labile or acid-stable linkers, the antitumor activity of CalichDM conjugated to m5/44, and its subsequent humanization by CDR grafting. Murine IgG1 mAb m5/44 was selected based on its subnanomolar affinity for CD22 and ability to be internalized into B cells. CalichDM conjugated to m5/44 caused potent growth inhibition of CD22+ human B-cell lymphomas (BCLs) in vitro. The conjugate of m5/44 with an acid-labile linker was more potent than an acid-stable conjugate, a nonbinding conjugate with a similar acid-labile linker, or unconjugated CalichDMH in inhibiting BCL growth. CalichDM conjugated to m5/44 caused regression of established BCL xenografts in nude mice. In contrast, both unconjugated m5/44 and a nonbinding conjugate were ineffective against these xenografts. Based on the potent antitumor activity of m5/44-CalichDM conjugates, m5/44 was humanized by CDR grafting to create g5/44, an IgG4 anti-CD22 antibody. Both m5/44 and g5/44 bound CD22 with subnanomolar affinity. Competitive blocking with previously characterized murine anti-CD22 mAbs suggested that g5/44 recognizes epitope A located within the first N-terminal Ig-like domain of human CD22. Antitumor efficacy of CalichDM conjugated to g5/44 against BCL xenografts was more potent than its murine counterpart. Based on these results, a calicheamicin conjugate of g5/44, CMC-544, was selected for further development as a targeted chemotherapeutic agent for the treatment of B-cell malignancies.

No abstract

A stratified random cluster sample of 15,845 subjects was performed in two regions of Nepal to determine the prevalence and main causes of hearing impairment (the most common disability) and the prevalence of ear disease. Subjects reporting current ear pain, or ear discharge, or hearing impairment on direct questioning by a Nepali health worker (primary screening failed), had otoscopy and audiometry (using the Liverpool Field Audiometer) performed, and a questionnaire administered relating to past history. In every fifth house subjects who passed the primary screening (1,716 subjects) were examined to assess the false negative rate of screening. An estimated 16.6 per cent of the study population have hearing impairment (either ear worse than 30 dB hearing threshold level (HTL) 1.0–4.0 kHz, or 50 dB HTL 0.5 kHz), and 7.4 per cent ear drum pathology, equivalent to respectively 2.71 and 1.48 million people extrapolated to the whole of Nepal. Most hearing impairment in the school age group (55.2 per cent) is associated with otitis media or its sequelae. Probably at least 14 per cent of sensorineural deafness is preventable (7 per cent infectious disease, 3.9 per cent trauma, 0.8 per cent noise exposure, 1 per cent cretinism, and 1 per cent abnormal pregnancy or labour). Most individuals reporting current ear pathology (61 per cent) had never attended a health post, and of those receiving ear drop treatment, 84 per cent still had serious pathology. Of subjects who reported ear drop treatment at any time, 31 per cent still had serious pathology. The use of traditional remedies was prevalent.In conclusion this study shows high prevalences of hearing impairment and ear drum pathology. To reduce hearing impairment in Nepal, particularly in the school age group, a priority should be the effective treatment of otitis media.