Monoclonal Antibodies: Past, Present and Future.

Monoclonal antibodies (mAbs) are immunoglobulins designed to target a specific epitope on an antigen. Immunoglobulins of identical amino-acid sequence were originally produced by hybridomas grown in culture and, subsequently, by recombinant DNA technology using mammalian cell expression systems. The antigen-binding region of the mAb is formed by the variable domains of the heavy and light chains and contains the complementarity-determining region that imparts the high specificity for the target antigen. The pharmacokinetics of mAbs involves target-mediated and non-target-related factors that influence their disposition.Preclinical safety evaluation of mAbs differs substantially from that of small molecular (chemical) entities. Immunogenicity of mAbs has implications for their pharmacokinetics and safety. Early studies of mAbs in humans require careful consideration of the most suitable study population, route/s of administration, starting dose, study design and the potential difference in pharmacokinetics in healthy subjects compared to patients expressing the target antigen.Of the ever-increasing diversity of therapeutic indications for mAbs, we have concentrated on two that have proved dramatically successful. The contribution that mAbs have made to the treatment of inflammatory conditions, in particular arthritides and inflammatory bowel disease, has been nothing short of revolutionary. Their benefit has also been striking in the treatment of solid tumours and, most recently, as immunotherapy for a wide variety of cancers. Finally, we speculate on the future with various new approaches to the development of therapeutic antibodies.

An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.

Comparing preferences for outcomes of psoriasis treatments among patients and dermatologists in the U.K.: results from a discrete-choice experiment.

BACKGROUND: Plaque psoriasis can have a significant negative effect on patients' quality of life, and treatments can result in serious toxicities. Although there have been several studies of patients' and physicians' relative preferences for the benefits and risks of psoriasis treatments, it is unclear how and whether patients' and physicians' preferences for the outcomes of psoriasis treatments differ. OBJECTIVES: To quantify patient and dermatologist preferences for improvements in psoriasis symptoms and for increases in the risk of treatment-related serious adverse events. METHODS: Members of the U.K. Psoriasis Association and U.K. dermatologists with experience prescribing biologics completed a web-enabled discrete-choice experiment survey in which they evaluated efficacy and safety features of biological treatments for psoriasis. Choices between hypothetical treatment options were used to estimate preference weights indicating respondents' relative trade-off preferences among treatment outcomes. These outcomes included improvements in the severity and coverage of psoriatic plaques and treatment-related risks of tuberculosis, serious infections and lymphoma. Preference estimates were used to derive the maximum level of side-effect risks that respondents would accept for improvements in psoriasis symptoms. RESULTS: Respondents' tolerance for side-effect risks varied with side-effect severity and location of plaques, and risk tolerance for serious side-effects was greater for patients than for dermatologists. CONCLUSIONS: Estimates of patients' risk tolerance for serious side-effects indicate that patients valued psoriasis symptom control highly and suggest that psoriasis symptoms have a significant effect on patients' quality of life. In light of research showing increased treatment satisfaction and improved treatment adherence among patients who receive therapies that are consistent with their preferences, our findings suggest that greater communication between dermatologists and patients about risk tolerance could help improve patient care.

Alterations in amygdala-prefrontal circuits in infants exposed to prenatal maternal depression.

Prenatal exposure to maternal depression is common and puts offspring at risk for developing a range of neuropsychiatric disorders. Despite its prevalence and adverse associations, neurobiological processes by which prenatal maternal depression (PMD) confers risk remain poorly understood. Maternal mood and fetal behavior were assessed between 34 and 37 gestational weeks. Using resting-state functional magnetic resonance imaging (fMRI) and diffusion MRI, we examined functional and structural connectivity within amygdala-prefrontal circuits in 64 infants (mean age=5.8±1.7 weeks) with (n=20) and without (n=44) in utero exposure to PMD. Resting fMRI and diffusion MRI both indicated atypical amygdala-prefrontal connectivity in PMD-exposed infants: Resting fMRI indicated increased inverse, or negative, functional connectivity between the amygdala and the dorsal prefrontal cortex (PFC), bilaterally, and diffusion MRI indicated decreased structural connectivity between the right amygdala and the right ventral PFC. Spectral dynamic causal modeling supported these findings suggesting altered amygdala-PFC effective (or directed) connectivity in PMD-exposed infants. Last, path analyses supported a mechanistic account relating PMD to a third-trimester fetal behavior: PMD alters amygdala-PFC connectivity, which in turn, is associated with an increase in fetal heart rate reactivity to in utero perturbation. These data suggest that the maturation and coordination of central and peripheral physiology are altered by prenatal exposure to maternal depression. To the best of our knowledge, this is the first study to directly associate infant MRI measures with a behavior-fetal heart rate response, and supports hypotheses that PMD-associated variations in the development of amygdala-PFC circuits are relevant for future neurobehavioral maturation.

Longitudinal magnetic resonance imaging reveals striatal hypertrophy in a rat model of long-term stimulant treatment.

Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, 'Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy.

Physician preferences for bone metastasis drug therapy in Canada.

BACKGROUND: Currently in Canada, several bone-targeted agents (btas) with varying characteristics are available for the prevention of skeletal-related events (sres) in patients with bone metastasis secondary to solid tumours. In the present study, we evaluated the preferences of physicians in Canada for the various attributes of the available btas. METHODS: Physicians treating patients with bone metastasis from solid tumours were invited to complete an online discrete-choice experiment. Respondents were asked to choose between pairs of hypothetical medications for virtual patients. Each hypothetical medication was described based on predefined key attributes: time until first sre, time until worsening of pain, medication-related annual risk of osteonecrosis of the jaw (onj), medication-related annual risk of renal impairment, and mode of administration. A random-parameters logit model was used to analyze the choices between hypothetical medications and thus infer physician preferences for medication attributes. RESULTS: Responses from the 200 physicians who completed the discrete-choice experiment suggested that months until first sre, risk of renal impairment, and months until worsening of pain were considered the most important attributes affecting choice of bta. The annual risk of onj was considered the least important attribute. CONCLUSIONS: When making treatment decisions about the choice of bta for patients with bone metastasis from solid tumours, delaying sres and worsening of pain, and reducing the risk of renal impairment are primary considerations for physicians in Canada.

Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.

BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.

Locomotion of electrocatalytic nanomotors due to reaction induced charge autoelectrophoresis.

Bimetallic rod-shaped nanomotors swim autonomously in hydrogen peroxide solutions. Here, we present a scaling analysis, computational simulations, and experimental data that show that the nanomotor locomotion is driven by fluid slip around the nanomotor surface due to electrical body forces. The body forces are generated by a coupling of charge density and electric fields induced by electrochemical reactions occurring on the nanomotor surface. We describe the dependence of nanomotor motion on the nanomotor surface potential and reaction-driven flux.

Development of leadership self-efficacy and collective efficacy: adolescent girls across castes as peer educators in Nepal.

Adolescent girls in Nepal face enormous social barriers to accessing education and health services due to exclusionary socio-religious traditions and years of conflict. The programme and study reported here address two issues that a national assembly of in-school and out-of-school adolescent girls, who had completed a basic life skills class, and, in the case of unschooled girls, an intensive literacy course, identified as important to their well-being - menstrual restrictions and HIV awareness and prevention. Local non-governmental organizations developed a peer education programme in three districts of Nepal that paired girls from different castes and different educational levels. The programme sought to increase peer educators' (PE) leadership and collective efficacy for informing peers and adults in their communities about the effects that these issues have on women and girls. In total, 504 girls were selected and trained as PEs. They conducted targeted discussion sessions with other girls and organised mass awareness events, reaching 20,000 people. Examination of the effects of participating in the programme on key outcome measures showed that leadership self-efficacy, which was a central theoretical construct for the programme, provided a strong predictor of both increased HIV knowledge and of practicing fewer menstrual restrictions at endline. The project demonstrated that girls from different caste and educational backgrounds are able to work together to change individual behaviour and to address socio-cultural norms that affect their lives and well-being within their communities.

Impact of preferential flow at varying irrigation rates by quantifying mass fluxes.

Solute concentration and soluble dye studies inferring that preferential flow accelerates field-scale contaminant transport are common but flux measurements quantifying its impact are essentially nonexistent. A tile-drain facility was used to determine the influence of matrix and preferential flow processes on the flux of mobile tracers subjected to different irrigation regimes (4.4 and 0.89 mm h(-1)) in a silt loam soil. After tile outflow reached steady state either bromide (Br; 280 kg ha(-1)) or pentafluorobenzoic acid (PFBA; 121 kg ha(-1)) was applied through the irrigation system inside a shed (3.5 x 24 m). Bromide fluxes were monitored at an irrigation rate of 4.4 mm h(-1) while PFBA fluxes were monitored at an irrigation rate of 0.89 mm h(-1). At 4.4 mm h(-1) nearly one-third of the surface-applied Br was recovered in the tile line after only 124 mm of irrigation and was poorly fit by the one-dimensional convective-dispersive equation (CDE). On the other hand, the one-dimensional CDE fit the main PFBA breakthrough pattern almost perfectly, suggesting the PFBA transport was dominated by matrix flow. Furthermore, after 225 mm of water had been applied, less than 2% of the applied PFBA had been leached through the soil compared with more than 59% of the applied Br. This study demonstrates that the methodology of applying a narrow strip of chemical to a tile drain facility is appropriate for quantifying chemical fluxes at the small-field scale and also suggests that there may be a critical input flux whereby preferential flow is initiated.

Clinical pharmacology studies in UK Phase 1 units: an AHPPI survey 1999-2000.

AIMS: This study, conducted by the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI), was designed to determine the amount of Phase 1 activity in the UK in the period 1999-2000, the timelines involved for submissions to ethics committee and responses from ethics committees. METHODS: A questionnaire was completed by AHIPPI members from pharmaceutical companies with in-house phase 1 units, by Clinical Research Organizations (CRO's) and by academic centres. A few responses were also vailable from organisations that were not AHPPI members. Results were rendered anonymous and grouped by category. RESULTS: The response rate was > 98% and indicated that the vast majority of early drug research in humans is now CRO-based (82%). The total number of studies (as indicated by protocol numbers) was notably similar across the 2 years--629 in 1999 and 606 in 2000. Turnaround time for ethics committee review was a mean of 14 days. CONCLUSIONS: These data set important benchmarks for early-phase drug research in the UK where regulatory approval is not currently required. Furthermore, the information should be used as a guide if the competitive nature of such work in the UK is to be maintained as new national legislation is implemented following publication of the European Union (EU) Clinical Trials Directive.

Les syndromes paranéoplasiques.

Paraneoplastic syndromes affecting the nervous system are rare but devastating complications of systemic cancer. The neurologic disorder usually precedes identification of the cancer and can affect any portion of the nervous system including cerebral cortex, cerebellum, spinal cord, peripheral nerves, neuromuscular junction or muscle. A single area or cell type of the nervous system may be affected or the entire neuraxis may be involved. The pathogenesis of paraneoplastic syndromes involving the nervous system is believed to be immune-mediated: the current hypothesis is that antigens usually expressed only in neurons are expressed in a cancer; the immune system recognizes the antigen in the cancer as foreign and mounts an immune response that slows the growth of the tumor but damages the nervous system. The diagnosis of a paraneoplastic syndrome is made either by identifying a small cancer in a patient with a neurologic disorder of unknown etiology or by identifying paraneoplastic autoantibodies in the serum of patients. The treatment involves identification and treatment of the causal cancer and immunosuppression to suppress both the humoral and cellular immune response.

Exposure to traffic among urban children injured as pedestrians.

OBJECTIVES: To explore the immediate pre-crash activities and the routine traffic exposure (street crossing and play) in a sample of urban children struck by automobiles. In particular, the traffic exposure of children who were struck while playing was compared with that of those struck while crossing streets. DESIGN: Cross sectional survey. SETTING: Urban pediatric emergency department. PATIENTS: A total of 139 children ages 4-15 years evaluated for acute injuries resulting from pedestrian-motor vehicle collisions during a 14 month period. MAIN OUTCOME MEASURES: Sites of outdoor play, daily time in outdoor play, weekly number of street crossings, pre-crash circumstance (play v walking). RESULTS: Altogether 39% of the children routinely used the street and 64% routinely used the sidewalks as play areas. The median number of street crossings per week per child was 27. There were no differences in exposures for the 29% who were hit while playing compared with the 71% who were hit while walking. Although 84% of the children walked to or from school at least one day per week, only 15% of the children were struck while on the school walking trip. The remainder were injured either while playing outdoors or while walking to other places. CONCLUSIONS: Urban children who are victims of pedestrian crashes have a high level of traffic exposure from a variety of circumstances related to their routine outdoor playing and street crossing activities. The distributions of traffic exposures were similar across the sample, indicating that the sample as a whole had high traffic exposure, regardless of the children's activity preceding the crash. Future pedestrian injury programs should address the pervasive nature of children's exposure to traffic during their routine outdoor activities.

Multiple interactions of cimetidine and probenecid with valaciclovir and its metabolite acyclovir.

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C(max)) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C(max) by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.

The photoreceptor cell-specific nuclear receptor is an autoantigen of paraneoplastic retinopathy.

OBJECTIVES: To report a novel antibody associated with paraneoplastic retinopathy and to characterize the retinal autoantigen. METHODS: Immunohistochemistry of rat and human tissues was used to identify antiretinal antibodies. Serologic screening of a bovine retinal cDNA expression library was performed to clone the target antigen. RESULTS: A 72-year-old woman presented with a 6-month history of progressive visual loss, bilateral central scotomas, light flashes, and night blindness. Visual acuity was 20/40 OD and 20/30 OS. There was generalized loss of retinal pigment and narrow arterioles; discs were normal in appearance. The electroretinogram showed no response. Chest computed tomograph scan demonstrated a right lung mass; biopsy revealed poorly differentiated carcinoma. The patients' serum contained antibodies that immunolabeled nuclei of cells of the outer--and to a lesser extent, the inner--nuclear layer of the adult rat retina. No reactivity was identified with nonretinal adult human or rat tissues. Reactivity was seen in the developing rat embryo. Serologic screening of a bovine retinal library resulted in the isolation of three overlapping clones, encoding a protein highly homologous to the human photoreceptor cell-specific nuclear receptor gene product. CONCLUSIONS: The target antigen of an antibody associated with paraneoplastic retinopathy is the photoreceptor cellspecific nuclear receptor, a member of a conserved family of nuclear receptors involved in photoreceptor cell development or maintenance.

Molecular and clinical diversity in paraneoplastic immunity to Ma proteins.

Antibodies to Ma1 and Ma2 proteins identify a paraneoplastic disorder that affects the limbic system, brain stem, and cerebellum. Preliminary studies suggested the existence of other Ma proteins and different patterns of immune response associated with distinct neurologic symptoms and cancers. In this study, our aim was to isolate the full-length sequence of Ma2 and new family members, identify the major autoantigen of the disorder, and extend the dinical-immunological analysis to 29 patients. Sera from selected patients were used to probe a brainstem cDNA library and isolate the entire Ma2 gene and a new family member, Ma3. Ma3 mRNA is ubiquitously expressed in brain, testis, and several systemic tissues. The variable cellular expression of Ma proteins and analysis of protein motifs suggest that these proteins play roles in the biogenesis of mRNA. Immunoblot studies identify Ma2 as the major autoantigen with unique epitopes recognized by all patients' sera. Eighteen patients had antibodies limited to Ma2: they developed limbic, hypothalamic, and brainstem encephalitis, and 78% had germ-cell tumors of the testis. Eleven patients had antibodies to Ma2 and additional antibodies to Ma1 and/or Ma3; they usually developed additional cerebellar symptoms and more intense brainstem dysfunction, and 82% of these patients had tumors other than germ-cell neoplasms. Overall, 17 of 24 patients (71%) with brain magnetic resonance imaging studies had abnormalities within or outside the temporal lobes, some as contrast-enhancing nodular lesions. A remarkable finding of immunity to Ma proteins is that neurologic symptoms may improve or resolve. This improvement segregated to a group of patients with antibodies limited to Ma2.