Sharks give a handle to potent anti-tumor multiparatopic antibodies inducing membrane depletion of PD-L1.

Despite the immense clinical success of the antibody therapeutics that neutralize programmed death receptor ligand 1 (PD-L1) and thus resurrect T cell antitumor activity, the patient response rates remain low. In this issue of Cell Chemical Biology, Ludwig et al.1 reveal novel topologies of multiparatopic antibodies that mediate potent PD-L1 downregulation.

Trispecific antibodies produced from mAb2 pairs by controlled Fab-arm exchange.

Bispecific antibodies and antibody fragments are therapeutics of growing importance. They are clinically applied for effector cell engagement, enhanced targeting selectivity, addressing of multiple cellular pathways and active transfer of certain activities into difficult-to-reach compartments. These functionalities could profit from a third antigen specificity. In this work we have employed symmetrical bispecific parental antibodies of mAb2 format, which feature a novel antigen binding site in the CH3 domains, and engineered them with a minimal number of point mutations to guide the formation of a controlled Fab-arm exchanged trispecific antibody at a high yield after reduction and re-oxidation. Two model antibodies, one reactive with EGFR, Her2 and VEGF, and one with Fab-arms binding to Ang2 and VEGF and an Fc fragment binding to VEGF, were prepared and examined for heterodimeric status, stability, antigen binding properties and biological activity. Resulting molecules were of good biophysical characteristics and retained antigen reactivity and biological activity of the parental mAb2 constructs.

Fluoroless Atrial Fibrillation Catheter Ablation: Technique and Clinical Outcomes.

Fluoroscopy continues to be considered an indispensable part of atrial fibrillation (AF) ablation worldwide. Deleterious effects of radiation exposure to patients, physicians, and catheter laboratory personnel are gaining increased consideration. Safety and efficacy of a fluoroless approach for AF ablation is comparable with outcomes achieved with fluoroscopy use. This article focuses on AF ablation with zero fluoroscopy use as well as current evidence on efficacy and safety of this technique. In contrast, minimal fluoroscopy is an alternative. Relying on intracardiac echocardiography for transseptal access and electroanatomic mapping for catheter manipulation can help implement this approach on a wider scale.

Clinical and economic impact of multipoint left ventricular pacing: A comparative analysis from the Italian registry on multipoint pacing in cardiac resynchronization therapy (IRON-MPP).

INTRODUCTION: Early evidence suggests that multipoint left ventricular pacing (MPP) may improve response to cardiac resynchronization therapy (CRT). It is unknown whether this benefit is sustained and cost-effective. We used real-world data to evaluate long-term impact of MPP-ON clinical status, heart failure hospitalizations (HFH) and costs. METHODS: The Italian registry on multipoint left ventricular pacing is a prospective, multicenter registry of patients implanted with MPP-enabled CRT devices. For this analysis, clinical and echocardiographic data were collected through 24 months and compared between patients with (MPP-ON) or without (MPP-OFF) early MPP activation at implant. The total cost of each HFH was estimated with national Italian reimbursement rates. RESULTS: The study included 190 MPP-OFF and 128 MPP-ON patients with similar baseline characteristics. At 1 and 2 years, the MPP-ON group had lower rates of HFH vs MPP-OFF (1-year hazard ratio [HR]: 0.14, P = .0014; 2-year HR: 0.38, P = .009). The finding persisted in a subgroup of patients with consistent MPP activation through follow-up (1-year HR: 0.19; P = .0061; 2-year HR: 0.39, P = .022). Total HFH per-patient costs were lower in the MPP-ON vs the MPP-OFF group at 1 year (€101 ± 50 vs €698 ± 195, P < .001) and 2 years (€366 ± 149 vs €801 ± 203, P = .038). More MPP-ON patients had ≥5% improvement in ejection fraction (76.8% vs 65.4%, P = .025) and clinical composite score (66.7% vs 47.5%, P = .01). CONCLUSIONS: In this multicenter clinical study, early MPP activation was associated with a significant reduction in cumulative HFH and related costs after 1 and 2 years of follow-up.

First Experience of Transcatheter Leak Occlusion With Detachable Coils Following Left Atrial Appendage Closure.

OBJECTIVES: The aim of this study was to assess the feasibility and efficacy of transcatheter leak closure with detachable coils in patients with incomplete left atrial appendage (LAA) closure. BACKGROUND: Incomplete LAA closure is common after interventional therapies targeting the LAA, potentially hindering effective thromboembolic prevention. Detachable coils have found a wide range of applications for transcatheter vascular occlusion and embolization procedures. METHODS: Thirty consecutive patients at high thromboembolic risk with clinically relevant residual leaks (mean age 72 ± 9 years, 73.3% men, mean CHA2DS2-VASc score 4.4 ± 1.4, mean HAS-BLED score 3.6 ± 0.8) underwent percutaneous closure of the LAA patency using embolization coils. Transesophageal echocardiography was performed at 60 ± 15 days post-procedure. RESULTS: LAA closure had been previously attempted with the Watchman device in 25 patients, the Amulet device in 2 patients, and the LARIAT device in 3 patients. Baseline transesophageal echocardiography documented moderate and severe leaks in 20 (66.7%) and 10 (33.3%) patients, respectively. After a single procedure, 25 patients (83.3%) showed complete LAA sealing or minimal leaks. Five patients (16.7%) had moderate residual leaks; 3 patients of them were offered repeat procedures. Mean procedure and fluoroscopy times were 76 ± 41 min and 21 ± 14 min, respectively; the mean volume of iodinated contrast medium used was 80 ± 47 ml. Coil deployment was successful in all cases. The overall complication rate was 6.1%. After a median follow-up period of 54 days (range 43 to 265 days) and an average of 1.1 procedures/patient, transesophageal echocardiography revealed complete LAA sealing or negligible residual leaks in 28 patients (93.3%; 25 with no residual leak, 3 patients with minimal to mild residual leaks) and moderate residual leaks in 2 patients (6.7%). CONCLUSIONS: Transcatheter LAA leak occlusion using endovascular coils appears to be a safe, effective, and promising approach in patients at high echo time risk with incomplete LAA closure. (Transcatheter Leak Closure With Detachable Coils Following Incomplete Left Atrial Appendage Closure Procedures [TREASURE]; NCT03503253).

Impact of multipoint pacing on projected battery longevity in cardiac resynchronization therapy. An IRON-MPP study sub-analysis.

BACKGROUND: Multipoint pacing (MPP) may improve clinical outcomes in patients with cardiac resynchronization therapy defibrillators (CRT-D), but its impact on battery longevity in a real-world population has not been investigated in large trials. OBJECTIVE: Compare projected battery longevity in CRT-D patients with and without MPP during long-term follow-up. METHODS: The Italian registry on multipoint left ventricular pacing (IRON-MPP) is a prospective, multicenter registry of patients implanted with MPP-capable CRT-D devices. Projected battery longevity during follow-up was compared for patients with MPP (MPP ON) vs single-site (MPP OFF) left ventricular pacing at CRT-D implantation. A sub-analysis excluded crossover patients with MPP activation or deactivation occurring after implantation. A second sub-analysis excluded patients with a right or left ventricular pacing amplitude >2.5 V. RESULTS: Out of 237 CRT-D patients (71 ± 9 years, 81% male) followed for 1.9 ± 0.8 years, 102 (43%) had MPP ON at implantation. Programmed atrial and ventricular outputs and percentage of pacing were similar between groups. MPP was associated with a 0.44 years reduction in projected battery longevity (P = .03) during long-term follow-up. Results were similar for the first and second sub-analyses, with a 0.57 years (P < .001) and 0.71 years (P < .001) reduction in projected longevity, respectively. CONCLUSION: In this long-term real-world registry, early MPP activation is associated with less than a 1-year reduction in projected battery life compared to single-site biventricular pacing.