The concept of exploiting the specific binding properties of monoclonal antibodies as a mechanism for selective delivery of cytotoxic agents to tumor cells is an attractive solution to the challenge ...of increasing the therapeutic index of cell-killing agents for treating cancer. All three parts of an antibody-drug conjugate (ADC)-the antibody, the cytotoxic payload, and the linker chemistry that joins them together-as well as the biologic properties of the cell-surface target antigen are important in designing an effective anticancer agent. The approval of brentuximab vedotin in 2011 for treating relapsed Hodgkin's lymphoma and systemic anaplastic large cell lymphoma, and the approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive metastatic breast cancer, have sparked vigorous research in the field, with >65 ADCs currently in clinical evaluation. This review highlights the ADCs that are approved for marketing, in pivotal clinical trials, or in at least phase II clinical development for treating both hematologic malignancies and solid tumors.
Despite considerable effort, application of monoclonal antibody technology has had only modest success in improving treatment outcomes in patients with solid tumours. Enhancing the cancer ...cell‐killing activity of antibodies through conjugation to highly potent cytotoxic ‘payloads’ to create antibody–drug conjuates (ADCs) offers a strategy for developing anti‐cancer drugs of great promise. Early ADCs exhibited side‐effect profiles similar to those of ‘classical’ chemotherapeutic agents and their performance in clinical trials in cancer patients was generally poor. However, the recent clinical development of ADCs that have highly potent tubulin‐acting agents as their payloads have profoundly changed the outlook for ADC technology. Twenty‐five such ADCs are in clinical development and one, brentuximab vedotin, was approved by the FDA in August, 2011, for the treatment of patients with Hodgkin's lymphoma and patients with anaplastic large cell lymphoma, based on a high rate of durable responses in single arm phase II clinical trials. More recently, a second ADC, trastuzumab emtansine, has shown excellent anti‐tumour activity with the presentation of results of a 991‐patient randomized phase III trial in patients with HER2‐positive metastatic breast cancer. Treatment with this ADC (single agent) resulted in a significantly improved progression‐free survival of 9.6 months compared with 6.4 months for lapatinib plus capecitabine in the comparator arm and significantly prolonged overall survival. Besides demonstrating excellent efficacy, these ADCs were remarkably well tolerated. Thus these, and other ADCs in development, promise to achieve the long sought goal of ADC technology, that is, of having compounds with high anti‐tumour activity at doses where adverse effects are generally mild.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Rare diseases, an emerging global public health priority, require an evidence-based estimate of the global point prevalence to inform public policy. We used the publicly available epidemiological ...data in the Orphanet database to calculate such a prevalence estimate. Overall, Orphanet contains information on 6172 unique rare diseases; 71.9% of which are genetic and 69.9% which are exclusively pediatric onset. Global point prevalence was calculated using rare disease prevalence data for predefined geographic regions from the 'Orphanet Epidemiological file' (http://www.orphadata.org/cgi-bin/epidemio.html). Of the 5304 diseases defined by point prevalence, 84.5% of those analysed have a point prevalence of <1/1 000 000. However 77.3-80.7% of the population burden of rare diseases is attributable to the 4.2% (n = 149) diseases in the most common prevalence range (1-5 per 10 000). Consequently national definitions of 'Rare Diseases' (ranging from prevalence of 5 to 80 per 100 000) represent a variable number of rare disease patients despite sharing the majority of rare disease in their scope. Our analysis yields a conservative, evidence-based estimate for the population prevalence of rare diseases of 3.5-5.9%, which equates to 263-446 million persons affected globally at any point in time. This figure is derived from data from 67.6% of the prevalent rare diseases; using the European definition of 5 per 10 000; and excluding rare cancers, infectious diseases, and poisonings. Future registry research and the implementation of rare disease codification in healthcare systems will further refine the estimates.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of highly cytotoxic agents, potentially reducing the severity of side effects by preferentially ...targeting their payload to the tumour site. ADCs are being increasingly used in combination with other agents, including as first-line cancer therapies. As the technology to produce these complex therapeutics has matured, many more ADCs have been approved or are in late-phase clinical trials. The diversification of antigenic targets as well as bioactive payloads is rapidly broadening the scope of tumour indications for ADCs. Moreover, novel vector protein formats as well as warheads targeting the tumour microenvironment are expected to improve the intratumour distribution or activation of ADCs, and consequently their anticancer activity for difficult-to-treat tumour types. However, toxicity remains a key issue in the development of these agents, and better understanding and management of ADC-related toxicities will be essential for further optimization. This Review provides a broad overview of the recent advances and challenges in ADC development for cancer treatment.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Highlights • Albeit their clinical success, ADCs have a relatively narrow therapeutic index. • Dose-limiting toxicities of ADCs are frequently unrelated to the targeted antigen. • Novel DNA damaging ...agents may increase the therapeutic index of ADCs. • Some ADCs can augment host immunity. • This provides a rationale for combining ADCs with immune-based therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Self-generated body movements require compensatory eye and head adjustments in order to avoid perturbation of visual information processing. Retinal image stabilization is traditionally ascribed to ...the transformation of visuovestibular signals into appropriate extraocular motor commands for compensatory ocular movements. During locomotion, however, intrinsic “efference copies” of the motor commands deriving from spinal central pattern generator (CPG) activity potentially offer a reliable and rapid mechanism for image stabilization, in addition to the slower contribution of movement-encoding sensory inputs.
Using a variety of in vitro and in vivo preparations of Xenopus tadpoles, we demonstrate that spinal locomotor CPG-derived efference copies do indeed produce effective conjugate eye movements that counteract oppositely directed horizontal head displacements during undulatory tail-based locomotion. The efference copy transmission, by which the extraocular motor system becomes functionally appropriated to the spinal cord, is mediated by direct ascending pathways. Although the impact of the CPG feedforward commands matches the spatiotemporal specificity of classical vestibulo-ocular responses, the two fundamentally different signals do not contribute collectively to image stabilization during swimming. Instead, when the CPG is active, horizontal vestibulo-ocular reflexes resulting from head movements are selectively suppressed.
These results therefore challenge our traditional understanding of how animals offset the disruptive effects of propulsive body movements on visual processing. Specifically, our finding that predictive efference copies of intrinsic, rhythmic neural signals produced by the locomotory CPG supersede, rather than supplement, reactive vestibulo-ocular reflexes in order to drive image-stabilizing eye adjustments during larval frog swimming, represents a hitherto unreported mechanism for vertebrate ocular motor control.
► A novel feedforward mechanism for gaze stabilization during vertebrate locomotion ► Locomotor efference copy drives compensatory eye movements in larval frogs ► The intrinsic CPG signals are conveyed directly to the extraocular motor nuclei ► The efference copy supersedes, rather than supplements, vestibulo-ocular reflexes
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chlorofluorocarbon (CFC) banks from uses such as air conditioners or foams can be emitted after global production stops. Recent reports of unexpected emissions of CFC-11 raise the need to better ...quantify releases from these banks, and associated impacts on ozone depletion and climate change. Here we develop a Bayesian probabilistic model for CFC-11, 12, and 113 banks and their emissions, incorporating the broadest range of constraints to date. We find that bank sizes of CFC-11 and CFC-12 are larger than recent international scientific assessments suggested, and can account for much of current estimated CFC-11 and 12 emissions (with the exception of increased CFC-11 emissions after 2012). Left unrecovered, these CFC banks could delay Antarctic ozone hole recovery by about six years and contribute 9 billion metric tonnes of equivalent CO
emission. Derived CFC-113 emissions are subject to uncertainty, but are much larger than expected, raising questions about its sources.
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