The IL-7R antagonist Lusvertikimab reduces leukemic burden in xenograft-ALL via antibody-dependent cellular phagocytosis.

Acute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of precursor B or T cells (BCP- or T-ALL). Current treatment protocols obtain high cure rates in children but are based on toxic polychemotherapy. Novel therapies are urgently needed, especially in relapsed/refractory (r/r) disease, high-risk leukemias and T-ALL, where immunotherapy approaches remain scarce. While the Interleukin-7 receptor (IL-7R) plays a pivotal role in ALL development, no IL-7R-targeting immunotherapy has yet reached clinical application in ALL. The IL-7Rα chain (CD127)-targeting IgG4 antibody Lusvertikimab (formerly OSE-127) is a full antagonist of the IL-7R pathway showing a good safety profile in healthy volunteers. Here, we show that ~85% of ALL cases express surface CD127. We demonstrate significant in vivo efficacy of Lusvertikimab immunotherapy in a heterogeneous cohort of BCP- and T-ALL patient-derived xenografts (PDX) in minimal residual disease (MRD) and overt leukemia models, including r/r and high-risk leukemias. Importantly, Lusvertikimab was particularly effective when combined with polychemotherapy in a phase 2-like PDX study with CD127high samples leading to MRD-negativity in >50% of mice treated with combination therapy. Mechanistically, Lusvertikimab targeted ALL cells via a dual mode of action comprising direct IL-7R antagonistic activity and induction of macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Lusvertikimab-mediated in vitro ADCP levels significantly correlated with CD127 expression levels and the reduction of leukemia burden upon treatment of PDX animals in vivo. Altogether, through its dual mode of action and good safety profile, Lusvertikimab may represent a novel immunotherapy option for any CD127-positive ALL, particularly in combination with standard-of-care polychemotherapy.

Facing Southern Ocean warming: Temperature effects on whole animal performance of Antarctic krill (Euphausia superba).

The ongoing environmental changes in the Southern Ocean may cause a dramatic decrease in habitat quality. Due to its central position in the food web, Antarctic krill (Euphausia superba) is a key species of the marine Antarctic ecosystem. It is therefore crucial to understand how increasing water temperatures affect important krill life-cycle processes. Here, a long-term (August - March) laboratory acclimation experiment at different temperature scenarios (0.5 °C, 1.5 °C, 2.5 °C, 3.5 °C, 5 °C, 7 °C) was performed and the effects of elevated temperatures on whole animal parameters (O2 consumption, body length, length of the digestive gland) were analyzed. The response of krill oxygen consumption to different experimental temperatures differed between acute/short-term and long-term acclimation. After 8 months, krill oxygen consumption remained unchanged up to temperatures of 3.5 °C and was significantly higher at temperatures > 3.5 °C. Krill acclimated to temperatures ≥ 3.5 °C were significantly smaller at the end of the experiment. Limited food intake and/or conversion may have contributed to this effect, especially pronounced after the onset of the reproductive period. In addition, the seasonal growth pattern in males differed from that of females. Together, our findings indicate that warming Southern Ocean waters are likely to increase metabolic rate in krill, possibly altering the amount of energy available for other important life-cycle processes, a finding directly related to future population dynamics and fisheries management.

The microbiome of the octocoral Lobophytum pauciflorum: minor differences between sexes and resilience to short-term stress.

Bacteria associated with marine invertebrates are thought to have a range of important roles that benefit the host including production of compounds that may exclude pathogenic microorganisms and recycling of essential nutrients. This study characterised the microbiome of a gonochoric octocoral, Lobophytum pauciflorum, and investigated whether either sex or environmental stresses influenced the diversity of the associated microbiome through amplicon profiling of the bacterial 16S rRNA gene. Sequences affiliated to Spirochaetaceae and Endozoicimonaceae dominated the microbiome of L. pauciflorum, representing 43% and 21% of the community, respectively. Among the dominant class affiliations, no sex-specific differences were detected, though unassigned sequences were at a 2-fold higher relative abundance in samples from female individuals than from males. These potentially novel sequences contributed to observed differences between sexes as detected by a multivariate analysis at the OTU level. Exposing L. pauciflorum fragments to increased temperature (31°C), decreased pH (7.9) or both stressors simultaneously for 12 days did not significantly alter the microbial community, indicating that the soft coral microbiome is relatively resilient to short-term environmental stress.

Age-related cellular changes in the long-lived bivalve A. islandica.

One of the biggest challenges to studying causes and effects of aging is identifying changes in cells that are related to senescence instead of simply the passing of chronological time. We investigated two populations of the longest living non-colonial metazoan, Arctica islandica, with lifespans that differed sixfolds. Of four investigated parameters (nucleic acid oxidation, protein oxidation, lipid oxidation, and protein instability), only nucleic acid oxidation increased with age and correlated with relative lifespan. Nucleic acid oxidation levels increased significantly faster and were significantly higher in the shorter-lived than the longer-lived population. In contrast, neither protein oxidation, lipid oxidation, nor protein stability changed over time. Protein resistance to unfolding stress when treated with urea was significantly lower overall in the shorter-lived population, and lipid peroxidation levels were higher in the longer-lived population. With the exception of nucleic acid oxidation, damage levels of A. islandica do not change with age, indicating excellent cellular maintenance in both populations. Since correlations between nucleic acid oxidation and age have also been shown previously in other organisms, and nucleic acid oxidation accumulation rate correlates with relative age in both investigated populations, nucleic acid oxidation may reflect intrinsic aging mechanisms.

Gene expression and physiological changes of different populations of the long-lived bivalve Arctica islandica under low oxygen conditions.

The bivalve Arctica islandica is extremely long lived (>400 years) and can tolerate long periods of hypoxia and anoxia. European populations differ in maximum life spans (MLSP) from 40 years in the Baltic to >400 years around Iceland. Characteristic behavior of A. islandica involves phases of metabolic rate depression (MRD) during which the animals burry into the sediment for several days. During these phases the shell water oxygen concentrations reaches hypoxic to anoxic levels, which possibly support the long life span of some populations. We investigated gene regulation in A. islandica from a long-lived (MLSP 150 years) German Bight population and the short-lived Baltic Sea population, experimentally exposed to different oxygen levels. A new A. islandica transcriptome enabled the identification of genes important during hypoxia/anoxia events and, more generally, gene mining for putative stress response and (anti-) aging genes. Expression changes of a) antioxidant defense: Catalase, Glutathione peroxidase, manganese and copper-zinc Superoxide dismutase; b) oxygen sensing and general stress response: Hypoxia inducible factor alpha, Prolyl hydroxylase and Heat-shock protein 70; and c) anaerobic capacity: Malate dehydrogenase and Octopine dehydrogenase, related transcripts were investigated. Exposed to low oxygen, German Bight individuals suppressed transcription of all investigated genes, whereas Baltic Sea bivalves enhanced gene transcription under anoxic incubation (0 kPa) and, further, decreased these transcription levels again during 6 h of re-oxygenation. Hypoxic and anoxic exposure and subsequent re-oxygenation in Baltic Sea animals did not lead to increased protein oxidation or induction of apoptosis, emphasizing considerable hypoxia/re-oxygenation tolerance in this species. The data suggest that the energy saving effect of MRD may not be an attribute of Baltic Sea A. islandica chronically exposed to high environmental variability (oxygenation, temperature, salinity). Contrary, higher physiological flexibility and stress hardening may predispose these animals to perform a pronounced stress response at the expense of life span.

Physiological responses to self-induced burrowing and metabolic rate depression in the ocean quahog Arctica islandica.

Arctica islandica is the longest-lived non-colonial animal found so far, and reaches individual ages of 150 years in the German Bight (GB) and more than 350 years around Iceland (IC). Frequent burrowing and physiological adjustments to low tissue oxygenation in the burrowed state are proposed to lower mitochondrial reactive oxygen species (ROS) formation. We investigated burrowing patterns and shell water partial pressure of oxygen (P(O(2))) in experiments with live A. islandica. Furthermore, succinate accumulation and antioxidant defences were recorded in tissues of bivalves in the normoxic or metabolically downregulated state, as well as ROS formation in isolated gills exposed to normoxia, hypoxia and hypoxia/reoxygenation. IC bivalves burrowed more frequently and deeper in winter than in summer under in situ conditions, and both IC and GB bivalves remained burrowed for between 1 and 6 days in laboratory experiments. Shell water P(O(2)) was <5 kPa when bivalves were maintained in fully oxygenated seawater, and ventilation increased before animals entered the state of metabolic depression. Succinate did not accumulate upon spontaneous shell closure, although shell water P(O(2)) was 0 kPa for over 24 h. A ROS burst was absent in isolated gills during hypoxia/reoxygenation, and antioxidant enzyme activities were not enhanced in metabolically depressed clams compared with normally respiring clams. Postponing the onset of anaerobiosis in the burrowed state and under hypoxic exposure presumably limits the need for elevated recovery respiration upon surfacing and oxidative stress during reoxygenation.