The preclinical pharmacology of the high affinity anti-IL-6R Nanobody (R) ALX-0061 supports its clinical development in rheumatoid arthritis

Introduction: The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody (R) with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology. Methods: ALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control. Results: ALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration. Conclusions: ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA

Linkage study of fibrinogen levels: the Strong Heart Family Study

<p>Abstract</p> <p>Background</p> <p>The pathogenesis of atherosclerosis involves both hemostatic and inflammatory mechanisms. Fibrinogen is associated with both risk of thrombosis and inflammation. A recent meta-analysis showed that risk of coronary heart disease may increase 1.8 fold for 1 g/L of increased fibrinogen, independent of traditional risk factors. It is known that fibrinogen levels may be influenced by demographic, environmental and genetic factors. Epidemiologic and candidate gene studies are available; but few genome-wide linkage studies have been conducted, particularly in minority populations. The Strong Heart Study has demonstrated an increased incidence of cardiovascular disease in the American Indian population, and therefore represents an important source for genetic-epidemiological investigations.</p> <p>Methods</p> <p>The Strong Heart Family Study enrolled over 3,600 American Indian participants in large, multi-generational families, ascertained from an ongoing population-based study in the same communities. Fibrinogen was determined using standard technique in a central laboratory and extensive additional phenotypic measures were obtained. Participants were genotyped for 382 short tandem repeat markers distributed throughout the genome; and results were analyzed using a variance decomposition method, as implemented in the SOLAR 2.0 program.</p> <p>Results</p> <p>Data from 3535 participants were included and after step-wise, linear regression analysis, two models were selected for investigation. Basic demographic adjustments constituted model 1, while model 2 considered waist circumference, diabetes mellitus and postmenopausal status as additional covariates. Five LOD scores between 1.82 and 3.02 were identified, with the maximally adjusted model showing the highest score on chromosome 7 at 28 cM. Genes for two key components of the inflammatory response, i.e. interleukin-6 and "signal transducer and activator of transcription 3" (<it>STAT3</it>), were identified within 2 and 8 Mb of this 1 LOD drop interval respectively. A LOD score of 1.82 on chromosome 17 between 68 and 93 cM is supported by reports from two other populations with LOD scores of 1.4 and 1.95.</p> <p>Conclusion</p> <p>In a minority population with a high prevalence of cardiovascular disease, strong evidence for a novel genetic determinant of fibrinogen levels is found on chromosome 7 at 28 cM. Four other loci, some of which have been suggested by previous studies, were also identified.</p

A heterozygous moth genome provides insights into herbivory and detoxification

How an insect evolves to become a successful herbivore is of profound biological and practical importance. Herbivores are often adapted to feed on a specific group of evolutionarily and biochemically related host plants1, but the genetic and molecular bases for adaptation to plant defense compounds remain poorly understood2. We report the first whole-genome sequence of a basal lepidopteran species, Plutella xylostella, which contains 18,071 protein-coding and 1,412 unique genes with an expansion of gene families associated with perception and the detoxification of plant defense compounds. A recent expansion of retrotransposons near detoxification-related genes and a wider system used in the metabolism of plant defense compounds are shown to also be involved in the development of insecticide resistance. This work shows the genetic and molecular bases for the evolutionary success of this worldwide herbivore and offers wider insights into insect adaptation to plant feeding, as well as opening avenues for more sustainable pest management.Minsheng You … Simon W Baxter … et al

Monsoons: global energetics and local physics as drivers of past, present and future monsoons

Global constraints on momentum and energy govern the structure of the zonal mean tropical circulation and rainfall. The continental-scale monsoon systems are also facets of a momentum- and energy-constrained global circulation, but their modern and paleo variability deviates substantially from that of the longitudinal mean through mechanisms neither fully understood nor well simulated. A framework grounded in global constraints yet encompassing the complexities of monsoon dynamics is needed to identify the causes of mismatch between theory, models, and observations and, ultimately, improve regional climate projection. In a first step towards this goal, disparate regional processes must be distilled into gross measures of energy flow in and out of continents and from the surface to the tropopause, so that monsoon dynamics may be coherently diagnosed across modern and paleo observations and across idealized and comprehensive simulations. Accounting for zonal asymmetries in the circulation, land/ocean differences in surface fluxes, and the character of convective systems, such a monsoon framework would integrate our understanding at all relevant scales: from the fine details of how moisture and energy are lifted in the updrafts of thunderclouds, up to the global circulations

Pemanfaatan Air Limbah dan Ekskreta : Patokan Untuk Perlindungan Kesehatan Masyarakat.

20a, 229 hal., bibl.; 21c

Identifikasi Senyawa Metabolit Sekunder Bakteri Pseudomonas alcaligenes dengan Metode Fourier Transform Infrared (FTIR) menggunakan Pelarut Metanol

Udang vaname (Litopenaeus vannamei) merupakan komoditas budidaya yang banyak diminati oleh masyarakat di Indonesia dan memiliki potensi sebagai produk unggulan di sektor budidaya. Upaya budidaya udang vaname telah banyak dilakukan oleh pembudidaya udang, seperti sistem budidaya secara intensif untuk memenuhi kebutuhan masyarakat Indonesia. Namun, terdapat berbagai macam permasalahan dalam melakukan sistem budidaya udang secara intensif, salah satunya yaitu serangan penyakit bakteri. Penyakit bakteri yang dapat menyerang udang disebabkan oleh kualitas air yang buruk serta tidak sesuai dengan standar daripada budidaya udang secara intensif. Penyakit pada udang yang disebabkan oleh serangan bakteri dapat menurunkan kualitas serta penurunan tingkat produksi udang vaname, bakteri tersebut adalah P. alcaligenes. Udang yang terinfeksi bakteri P. alcaligenes memiliki ciri seperti bintik-bintik hitam yang terdapat di area karapas udang vaname. Bakteri P. alcaligenes dapat menyebabkan penyakit black spot pada udang vaname. Black spot merupakan pembentukan melanin pada karapas udang vaname yang akan membentuk bintik hitam pada karapas udang vaname. Senyawa melanin dibentuk oleh enzim PPO yang akan mengoksidasi fenol menjadi quinon. Fenol merupakan senyawa metabolit sekunder yang merupakan bagian dari senyawa fenolik. Senyawa metabolit sekunder dapat diidentifikasi dengan uji spektrofotometer FTIR, pengujian ini dilakukan untuk mengetahui apakah terdapat senyawa metabolit sekunder fenol pada bakteri P. alcaligenes yang dapat menyebabkan penyakit black spot pada udang vaname. Penelitian dilaksanakan pada bulan November – Desember 2021 di Laboratorium Parasit dan Penyakit Ikan serta Laboratorium Eksplorasi Sumberdaya Perikanan dan Kelautan, Fakultas Perikanan dan Ilmu Kelautan Universitas Brawijaya. Kepadatan awal dari bakteri P. alcaligenes yaitu 18 x 108 CFU/ml, kepadatan bakteri P. alcaligenes yang digunakan pada penelitian ini yaitu 105 CFU/ml, 106 CFU/ml dan 107 CFU/ml. Hasil uji dengan menggunakan FTIR didapatkan senyawa fenol pada kepadatan 18 x 105 CFU/ml dengan bilangan gelombang 3455,410 cm-1, kepadatan 18 x 106 CFU/ml dengan bilangan gelombang 3459,513 cm-1 dan kepadatan 18 x 107 CFU/ml dengan bilangan gelombang 3386,884 cm-