BackgroundARTISTRY-1 is an ongoing Phase 2/3 study evaluating the safety and efficacy of once-daily oral bictegravir (BIC) + lenacapavir (LEN) in virologically suppressed (VS; HIV-1 RNA <50 copies/mL) participants on complex antiretroviral (ARV) regimens. Here, we report Week 96 extension-phase data after transition to BIC/LEN single-tablet regimen (STR).MethodsParticipants without known integrase strand-transfer inhibitor (INSTI) resistance were randomized (2:2:1) to BIC + LEN (75mg + 25mg or 75mg + 50mg) or stable background regimen, respectively. At the end of randomized treatment (mean of 69 weeks from baseline), participants could choose to enter the extension period and receive BIC/LEN 75/50 mg STR. Baseline resistance-associated mutations (RAMs) were evaluated from cumulative historical genotypic reports (HGRs) and Day 1 proviral DNA genotyping using a composite baseline sequence. Resistance testing was performed for confirmed virologic rebound.ResultsOf 128 randomized/dosed participants, 119 entered the extension period and received BIC/LEN STR for a median time of 96 weeks (range 11-109) from end of randomization to cutoff date. Baseline RAMs were common (nucleoside reverse transcriptase inhibitor 82%, non-nucleoside reverse transcriptase inhibitor 66%, protease inhibitor 47%; INSTI RAMs 9% (proviral DNA)). Two participants met criteria for resistance testing before resuppressing, with no treatment-emergent capsid or integrase RAMs. All 119 participants were suppressed at last observed visit.ConclusionsDurable viral suppression was maintained for up to 96 weeks in the Phase 2 extension, with all participants in the extension phase maintaining virologic suppression and no treatment-emergent resistance to study drugs, supporting long-term virologic durability of BIC/LEN STR in VS individuals on complex ART.
Objective The objective was to evaluate the safety, pharmacokinetics and efficacy of an alternative deltoid site for CAR-LA. Design This is a prospective cohort of people living with HIV (PLWHIV) switching for intramuscular long acting cabotegravir and rilpivirine (CAR-LA). Methods Clinical and biological data were collected at baseline, month 1 (M1), month 3 (M3), and every three months thereafter, when available. Results A total of 15 patients were enrolled between August 2022 and October 2024. Of these, 11 were transgender women, 1 cisgender woman, and 3 cisgender males. The median duration of plasma HIV-1-RNA (pVL) <50 copies/mL before switching to CAR-LA was 42 months. The main criterion for selecting PLWHIV was the presence of injected silicone in the gluteal region (12 out of 15 cases). Median duration of CAR-LA was 13 months. All patients maintained a pVL<50 copies/mL at M1 and M3. No virological failure was observed in the 13 patients who were followed up to M12. One PLWHIV discontinued deltoid injections due to low plasma concentrations at M2, while another discontinued due to non-adherence which led to cabotegravir resistance at M13. Three PLWHIV reported moderate pain at the injection site, with one discontinuing treatment at M12. All CAB and RPV plasma concentrations measured after deltoid CAR-LA were comparable with those obtained following gluteal CAR-LA phase 3 studies. Conclusion Deltoïd CAR-LA seems to be a reliable and well-tolerated alternative for PLWHIV with contraindications for gluteal injections.
Background Posttransplant cytomegalovirus (PT-CMV) infection remains a challenging complication and a major cause of morbidity and mortality in transplant recipients. Methods This cross-sectional study surveyed physicians treating solid organ and hematopoietic stem cell transplantation recipients from Central and Eastern European countries. Physician-reported CMV infection prevalence in transplant recipients, treatment regimens, and unmet needs for managing patients with refractory with/without resistance (R+/R-) PT-CMV infection were assessed. Results Overall, 164 physicians completed the survey, 23.8% of whom were nephrologists. Physicians estimated that 26.4% of patients who received a transplant in the past 12 months developed PT-CMV infection, of whom 12.9% had refractory R+/R- PT-CMV infection. On average, 66.5%, 16.5%, and 4.0% of physicians’ current patients with PT-CMV infection received first-, second-, and third- or later-line treatments, respectively. Physicians considered maintenance of CMV viremia clearance (94.5%), good symptom control (94.5%), and lack of renal toxicity (93.9%) as moderately-to-extremely important treatment attributes for managing PT-CMV infection. Compared with other available treatments, more physicians indicated oral valganciclovir to have a strong-to-complete association with these treatment attributes. Overall, 63.4% of physicians indicated some level of satisfaction with conventional refractory R+/R- PT-CMV treatments. However, 54.9% of physicians reported limited experience with newly approved therapies, such as maribavir. Most physicians considered limited treatment options as a major barrier for improving patient outcomes. Conclusion Survey findings of physicians treating transplant recipients in Central and Eastern Europe suggest the need for increased awareness of newly approved therapies with better efficacy and less toxicity for refractory R+/R- PT-CMV infection.
Background: Transferrin receptor protein 1 (TfR1) plays a central role in cellular iron uptake and is frequently overexpressed in malignant tumor cells, rendering it an attractive target for tumor-directed therapy and drug delivery. Methods: A fully human single-chain variable fragment (scFv) antibody targeting TfR1, termed T8scFv, was isolated from a human scFv phage display library through three rounds of stringent biopanning and subsequently reformatted into a full-length IgG1 antibody (T8IgG1). Binding kinetics were characterized using Octet biolayer interferometry (BLI), while cellular binding and internalization were assessed by flow cytometry and immunofluorescence microscopy, respectively. T8IgG1 was further conjugated to DT3C, a recombinant truncated diphtheria toxin fusion protein, to evaluate its internalization-dependent cytotoxicity in vitro. Results: T8scFv exhibited nanomolar affinity for TfR1 (KD = 214 ± 1 nM), which was substantially enhanced following conversion to the IgG1 format (T8IgG1, KD = 18.5 ± 0.1 nM). T8IgG1 specifically recognized TfR1 on the surface of tumor cells and underwent efficient TfR1-mediated internalization. The T8IgG1-DT3C complex significantly reduced cell viability and induced apoptosis in K562 cells in vitro. Conclusions: These findings indicate that T8IgG1 is a moderate-affinity, internalizing anti-TfR1 antibody and highlight its potential as a promising candidate for TfR1-based targeted antitumor drug delivery systems.
Background/Objectives: Antibodies are a rapidly expanding field in drug discovery, but their monospecificity limits therapeutic applications, particularly in complex inflammatory diseases. Multispecific therapeutics, which combine variable regions targeting two or more antigens, offer potential advantages such as enhanced efficacy, broader target modulation, and reduced side effects. This study aimed to identify and characterize bispecific, VHH-based antibodies simultaneously targeting IL-6 and IL-17A-two key cytokines involved in autoimmune and chronic inflammatory conditions. Methods: A phage display screening was conducted using llama-derived VHH libraries to select binders against human IL-6 and IL-17A. Binding affinities of individual VHHs and assembled bispecific constructs were assessed using Bio-Layer Interferometry (BLI). Functional activity was evaluated using reporter cell lines responsive to IL-6 and IL-17A signaling. Biophysical and quality assessments of selected VHHs and bispecific antibodies were performed using the Uncle screening platform and LabChip capillary electrophoresis. Results: Several high-affinity VHH binders were identified for both IL-6 and IL-17A, and incorporated into bispecific antibody formats. The bispecific candidates exhibited simultaneous inhibition of both cytokine pathways in functional reporter assays. Biophysical characterization confirmed good stability and purity profiles for selected molecules. Conclusions: This study demonstrates the feasibility of generating stable, functional bispecific VHH-based antibodies targeting IL-6 and IL-17A. These constructs show potential as therapeutic agents for treating autoimmune and chronic inflammatory diseases by modulating multiple signaling pathways simultaneously.
