Functional electrical stimulation combined with voluntary cycling accentuates VO2 response in people with severe multiple sclerosis: A pilot study.

BACKGROUND: Lower limb muscle weakness and reduced balance due to disease progression in multiple sclerosis (MS) may make robust aerobic exercise difficult. Functional electrical stimulation (FES) cycling combined with voluntary cycling may allow people with severe MS to enhance the intensity of aerobic exercise. The aim of this study was to investigate the cardiorespiratory, power, and participant-reported perceptions during acute bouts of FES cycling, voluntary cycling, and FES cycling combined with voluntary cycling (FES assist cycling). METHODS: Participants with severe MS (Expanded Disability Status Scale [EDSS] ≥ 6.0) undertook three exercise trials on a leg cycle ergometer. Trial 1 involved 30 min of FES cycling; Trial 2 involved two 10-minute bouts of voluntary cycling separated by 10 min rest; and Trial 3 was a combination of trials 1 and 2 (FES assist cycling). Outcome measures included VO2 (volume of oxygen consumption), cycle power output, heart rate, RPE, and post-exercise perceptions of pain and fatigue. RESULTS: Ten people with severe MS participated (9 female; age 52.4 ± 9.98 y; EDSS 7.1 ± 0.6). The average VO2 during the 30-minute trials was significantly higher for FES assist cycling compared to voluntary cycling (429.7 ± 111.0 vs 388.5 ± 101.0 mL/min, 95% CI 23.4 to 113.0 mL/min, p = 0.01), with a large effect size (Hedges' g = 1.04). Participants reported similar rates of perceived exertion at the end of FES cycling (13 ± 2), voluntary cycling (14 ± 2), and FES assist cycling (15 ± 1); p = 0.14. Self-reported pain was higher during both FES cycling (5.4 vs 0.3; 95% CI 3.4 to 6.7, p = 0.01, Hedges' g = 2.07) and FES assist cycling (4.2 vs. 0.3; 95% CI 2.3 to 5.5, p = 0.01, Hedges' g = 1.71) than voluntary cycling, both with large effect sizes. There was no difference in self-reported fatigue at the end of each trial (p = 0.21). CONCLUSION: This study found FES assist cycling produced significantly higher VO2 values than voluntary cycling, although the clinical significance of these differences is unknown. Participants performed FES assist cycling at a self-reported RPE consistent with moderate to vigorous intensity, however it was considered light-intensity exercise when expressed by METS. FES assist cycling was no more fatiguing post-exercise than the other modes.

A BCMA/CD16A bispecific innate cell engager for the treatment of multiple myeloma.

Despite the recent progress, multiple myeloma (MM) is still essentially incurable and there is a need for additional effective treatments with good tolerability. RO7297089 is a novel bispecific BCMA/CD16A-directed innate cell engager (ICE®) designed to induce BCMA+ MM cell lysis through high affinity binding of CD16A and retargeting of NK cell cytotoxicity and macrophage phagocytosis. Unlike conventional antibodies approved in MM, RO7297089 selectively targets CD16A with no binding of other Fcγ receptors, including CD16B on neutrophils, and irrespective of 158V/F polymorphism, and its activity is less affected by competing IgG suggesting activity in the presence of M-protein. Structural analysis revealed this is due to selective interaction with a single residue (Y140) uniquely present in CD16A opposite the Fc binding site. RO7297089 induced tumor cell killing more potently than conventional antibodies (wild-type and Fc-enhanced) and induced lysis of BCMA+ cells at very low effector-to-target ratios. Preclinical toxicology data suggested a favorable safety profile as in vitro cytokine release was minimal and no RO7297089-related mortalities or adverse events were observed in cynomolgus monkeys. These data suggest good tolerability and the potential of RO7297089 to be a novel effective treatment of MM patients.

Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy.

Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform the field of medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) in the chemical literature, enable the controlled degradation of specific proteins via their direction to the cellular proteasome. In this report, we describe the second phase of our research focused on exploring antibody-drug conjugates (ADCs), which incorporate BRD4-targeting chimeric degrader entities. We employ a new BRD4-binding fragment in the construction of the chimeric ADC payloads that is significantly more potent than the corresponding entity utilized in our initial studies. The resulting BRD4-degrader antibody conjugates exhibit potent and antigen-dependent BRD4 degradation and antiproliferation activities in cell-based experiments. Multiple ADCs bearing chimeric BRD4-degrader payloads also exhibit strong, antigen-dependent antitumor efficacy in mouse xenograft assessments that employ several different tumor models.