Monoclonal IgG Research Articles

Multiple Myeloma in a Young Patient Revealed by Lumbosciatica: A Case Report

Multiple myeloma, a malignant hematologic disorder characterized by excessive monoclonal plasma cell proliferation in the bone marrow, is rare in individuals under 40, comprising less than 2% of cases. This report details a 27-year-old patient with left-sided lumbosciatica and clinical signs of lumbar and radicular syndrome at the S1 level. Imaging revealed multiple osteolytic lesions with perilesional sclerosis and abnormalities in the first sacral foramen. Biological findings included normochromic normocytic anemia, hypercalcemia, elevated sedimentation rate, monoclonal IgG Kappa, free Kappa light chains, hyperproteinemia, and hypoalbuminemia. A bone marrow biopsy confirmed 95% plasma cell infiltration. The patient underwent a VRD regimen and three cycles of D-VRD and is awaiting autologous stem cell transplantation. This case underscores the need to consider multiple myeloma in young patients, as failure to do so could delay critical diagnosis and treatment.

First-in-human study on tolerability, pharmacokinetics and pharmacodynamics of single and multiple escalating doses of XKH001, a recombinant humanized monoclonal antibody against IL-25 in healthy Chinese volunteers

Background: XKH001 is a recombinant humanized IgG1 monoclonal antibody against IL-25 for the treatment of type 2 inflammatory diseases. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of XKH001 in humans for the first time. Research design and methods: This clinical investigation adopted a randomized, double-blind, and placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) design. Results: XKH001 was well tolerated in healthy Chinese subjects. Following repeated administration, XKH001 showed a slow absorption with a median Tmax of 4–7 days and a mean half-life (t1/2) of 22–25 days. The accumulation ratio ranged from 1.34 to 1.99. The exposure was mostly dose proportional, with a mean slope of 0.85–1.06. All subjects tested negative for ADA (except three subjects tested positive). The subjects who received 600 mg XKH001 in the MAD study showed a 78.2 ng/mL decrease in the total immunoglobulin E (IgE) level 85 days after the first administration, while the subjects who received matched placebo exhibited only a 8.6 ng/mL decrease.Conclusions: XKH001 showed favorable safety and pharmacokinetics profiles and a low immunogenicity in its first-in-human study. The data support its further clinical evaluation in patients with type 2 inflammatory diseases.

Long-Term Safety and Efficacy of Bimekizumab in Axial Spondyloarthritis: 2-Year Results from Two Phase 3 Studies.

Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)‑17F in addition to IL-17A, previously demonstrated efficacy and was well tolerated to 1 year in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA). Here, we report bimekizumab safety and efficacy to 2 years. Patients completing week 52 in the phase 3 studies BE MOBILE 1 (nr-axSpA; NCT03928704) and 2 (r‑axSpA; NCT03928743) were eligible for an ongoing open‑label extension (OLE; NCT04436640). All OLE patients received subcutaneous bimekizumab 160 mg every 4 weeks. Safety outcomes for patients who received ≥1 bimekizumab dose, and efficacy outcomes for all randomised patients, are reported to week 104. In the OLE (Weeks 52 - 104), 70.8% (367/518) of patients reported ≥1 treatment‑emergent adverse event (TEAE). Most frequent TEAEs (EAIR/100PY) were SARS-CoV-2 (COVID-19) infection (25.2), nasopharyngitis (11.0) and oral candidiasis (5.4). Fungal infection EAIR/100PY was 11.8 (majority Candida infections: 6.8; most mild/moderate, none serious/systemic). Inflammatory bowel disease and uveitis rates were low; no major adverse cardiovascular events or deaths occurred. TEAE incidence rate was generally similar across Weeks 0-52 and 52-104.At week 104, >50% of randomised patients (N = 586) achieved ASAS40; ∼60% achieved ASDAS low disease activity (<2.1) and >30% achieved ASDAS inactive disease (<1.3). Bimekizumab demonstrated sustained suppression of MRI inflammation at week 104, with >57% of patients achieving MRI remission. The safety profile of bimekizumab remained consistent with prior reports, with no new safety signals identified. 1-year efficacy was sustained to 2 years across patients with nr‑axSpA and r-axSpA.

SIV Env RhmAbs + N-803 at ART initiation prolongs viral decay without disrupting reservoir establishment in SIV-infected infant macaques.

The latent viral reservoir remains the major barrier to HIV cure, placing the burden of strict adherence to antiretroviral therapy (ART) on people living with HIV to prevent recrudescence of viremia. For infants with perinatally acquired HIV, adherence is anticipated to be a lifelong need. In this study, we tested the hypothesis that administration of ART and viral Envelope-specific rhesus-derived IgG1 monoclonal antibodies (RhmAbs) with or without the IL-15 superagonist N-803 early in infection would limit viral reservoir establishment in SIV-infected infant rhesus macaques. Following initiation of ART at 1-2 weeks after oral SIVmac251 infection, we observed biphasic decay of viremia, with first phase decay significantly faster in the ART + SIV RhmAbs-treated group compared to controls that received only ART. In contrast, the addition of N-803 to ART + SIV RhmAbs significantly slowed both the first and second phase viral decay compared to the ART only group. Treatment with a single dose of N-803 resulted in increased frequency of Ki67 expressing NK, CD8+, and CD4+ T cells. Levels of intact SIV proviruses in CD4+ T cells from blood, lymph nodes, and rectum at week 48 of ART did not differ across groups. Similarly, the time to viral rebound following ART interruption was not impacted by the experimental treatments. These results support the concept that the rebound-competent viral reservoir is formed within days after infection and that targeting only productively infected cells for clearance near the time of ART initiation, even during acute infection, may be insufficient to limit reservoir establishment.

Substructure-Specific Antibodies Against Fentanyl Derivatives.

Structural variants of the synthetic opioid fentanyl are a major threat to public health. Following an investigation showing that many derivatives are poorly detected by commercial lateral flow and related assays, we created hapten conjugate vaccines using an immunogenic virus-like particle carrier and eight synthetic fentanyl derivatives designed to mimic the structural features of several of the more dangerous analogues. Immunization of mice elicited strong antihapten humoral responses, allowing the screening of hundreds of hapten-specific hybridomas for binding strength and specificity. A panel of 13 monoclonal IgG antibodies were selected, each showing a different pattern of recognition of fentanyl structural variations, and all proving to be highly efficient at capturing parent fentanyl compounds in competition ELISA experiments. These results provide antibody reagents for assay development as well as a demonstration of the power of the immune system to create binding agents capable of both broad and specific recognition of small-molecule targets.

A novel interleukin-10 antibody graft to treat inflammatory bowel disease.

Inflammatory bowel disease (IBD) consists of chronic conditions that severely impact a patient's health and quality of life. Interleukin-10 (IL-10), a potent anti-inflammatory cytokine has strong genetic links to IBD susceptibility and has shown strong efficacy in IBD rodent models, suggesting it has great therapeutic potential. However, when tested in clinical trials for IBD, recombinant human IL-10 (rhIL-10) showed weak and inconsistent efficacy due to its short half-life and pro-inflammatory properties that counteract the anti-inflammatory efficacy. Here we present an engineered, IL-10, antibody-graft therapeutic (GFT-IL10M) designed to rectify these issues. GFT-IL10M combines the half-life extension properties of a monoclonal IgG antibody with altered IL-10 cell-type selective signaling, retaining desirable signaling on monocytes while reducing unwanted signaling on T, natural killer (NK), and B cells. Our structural and biochemical results indicate that the altered IL-10 topology in GFT-IL10M leads to a predominantly anti-inflammatory profile, potentially altering cell-type specific signaling patterns and extending half-life.

Distinctive roles of aquaporins and novel therapeutic opportunities against cancer.

Aquaporins (AQPs) are integral membrane proteins responsible for facilitating the transmembrane transport of water and small solutes. Their involvement in diverse physiological functions extends to pathological conditions, including cancer, positioning them as promising targets for anticancer therapy. Tumor cells, particularly those with high metastatic potential, exhibit elevated AQP expression, reinforcing their critical role in tumor biology. Emerging evidence highlights AQPs' involvement in key oncogenic processes such as cell migration, proliferation, and tumor-associated edema, suggesting their potential as novel therapeutic targets. Despite this, the development of selective and potent AQP inhibitors has proven challenging. Efforts to produce small-molecule AQP inhibitors have largely been unsuccessful. However, recent advancements include monoclonal human IgG antibodies targeting extracellular domains of aquaporin-4, offering new therapeutic strategies, particularly in glioblastoma, where AQP-4 is overexpressed. However, recent advancements include monoclonal human IgG antibodies targeting extracellular domains of aquaporin-4, offering new therapeutic strategies, particularly in glioblastoma, where AQP-4 is over expressed. These antibodies hold promise for selectively targeting and eradicating AQP-4-expressing cells in malignant brain tumors. This review discusses the critical role AQPs play in cancer, including their contributions to tumor cell proliferation, migration, angiogenesis, and edema formation. Additionally, we explore innovative therapeutic approaches, such as antibody-based interventions, and outline potential future research directions in AQP-targeted cancer therapies.

Arthritis induced by dupilumab treatment: A case report and literature review

Dupilumab is a human monoclonal IgG4 antibody targeting the interleukin-4 receptor alpha chain (IL-4Rα). It effectively inhibits the signaling pathways of both interleukin-4 (IL-4) and interleukin-13 (IL-13) and has been extensively employed in managing conditions such as atopic dermatitis, asthma, allergic rhinitis, and other allergic disorders. Despite numerous studies affirming its safety profile, suppression of IL-4 and IL-13 has been linked to an increased dominance of interleukin-17 (IL-17), which can lead to adverse effects resembling those seen in psoriatic arthritis and spondyloarthropathy-like symptoms. Through a case study of a patient receiving dupilumab for prurigo nodularis, this paper seeks to shed light on the potential inflammatory disease-like side effects associated with this treatment. Specifically, we explore manifestations such as enthesitis/arthritis, psoriasis, uveitis, inflammatory bowel disease, lupus erythematosus, and vasculitis, urging vigilance among rheumatologists and dermatologists.

Exploring the Interaction of Biotinylated FcGamma RI and IgG1 Monoclonal Antibodies on Streptavidin-Coated Plasmonic Sensor Chips for Label-Free VEGF Detection.

Vascular endothelial growth factor (VEGF) is a critical angiogenesis biomarker associated with various pathological conditions, including cancer. This study leverages pre-biotinylated FcγRI interactions with IgG1-type monoclonal antibodies to develop a sensitive VEGF detection method. Utilizing surface plasmon resonance (SPR) technology, we characterized the binding dynamics of immobilized biotinylated FcγRI to an IgG1-type antibody, Bevacizumab (AVT), through kinetic studies and investigated suitable conditions for sensor surface regeneration. Subsequently, we characterized the binding of FcγRI-captured AVT to VEGF, calculating kinetic constants and binding affinity. A calibration curve was established to analyze the VEGF quantification capacity and accuracy of the biosensor, computing the limits of blank, detection, and quantification at a 95% confidence interval. Additionally, the specificity of the biosensor for VEGF over other protein analytes was assessed. This innovative biomimetic approach enabled FcγRI-mediated site-specific AVT capture, establishing a stable and reusable platform for detecting and accurately quantifying VEGF. The results indicate the effectiveness of the plasmonic sensor platform for VEGF detection, making it suitable for research applications and, potentially, clinical diagnostics. Utilizing FcγRI-IgG1 antibody binding, this study highlights the industrial and clinical value of advanced biosensing technologies, offering insights to enhance therapeutic monitoring and improve outcomes in anti-VEGF therapies.

Xeligekimab: First Approval.

Xeligekimab (Jinlixi®) is a recombinant human interleukin (IL)-17A-neutralizing immunoglobulin (Ig)G4 monoclonal antibody being developed by Genrix (Shanghai) Biopharmaceutical for the treatment of plaque psoriasis, axial spondyloarthritis and lupus nephritis. Xeligekimab binds to IL-17A and blocks its interaction with the IL-17A receptor, thereby inhibiting the release of C-X-C motif chemokine ligand1 and IL-6. On 27 August 2024, xeligekimab received approval in China for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Xeligekimab is under regulatory review in China for the treatment of axial spondyloarthritis and is undergoing phaseII development for the treatment of lupus nephritis. This article summarizes the milestones in the development of xeligekimab leading to this first approval for plaque psoriasis.

Half-Life Extension of the IgG-Degrading Enzyme (IdeS) Using Fc-Fusion Technology.

Imlifidase (IdeS) is a bacterial protease that hydrolyzes human IgG in their hinge region, decreasing their half-life and abrogating their Fc-mediated properties. It is now successfully used in therapy to prevent graft rejection during kidney transplants and is being clinically evaluated in several IgG-mediated autoimmune diseases. IdeS short half-life however limits its clinical use, particularly in the case of chronic diseases that would request repeated administrations. Here, we developed IdeS-Fc fusion proteins as a divalent homodimer (IdeS-Fcdiv) or a monovalent heterodimer (IdeS-Fcmonov), in order to extend the IgG-depleting action of IdeS over time. Both IdeS-Fc efficiently separated monoclonal and polyclonal human IgG into F(ab')2 and Fc fragments, although with slower kinetics than their native counterpart. IdeS-Fcmonov exhibited a seven-fold half-life extension in vivo as compared with IdeS, and a significantly better residual cleavage of human IgG at later time points after injection. Our results provide proof of concept for the use of an IdeS with extended IgG-hydrolyzing functions in vivo that could rapidly translate to the clinic.

Evaluation of the effect of rozanolixizumab on pregnancy outcomes and pre- and postnatal development in cynomolgus monkeys.

Rozanolixizumab, a humanised immunoglobulin (Ig) G4 monoclonal antibody that selectively inhibits binding of IgG to the neonatal Fc receptor (FcRn), was evaluated in an embryo-foetal enhanced pre- and postnatal development (ePPND) study. Pregnant female cynomolgus monkeys (19 per group) received subcutaneous rozanolixizumab 50mg/kg or 150mg/kg or vehicle every 3 days from gestation day 20 until delivery. The proportion of pregnancy losses was 15.8%, 21.1% and 5.3%, in the rozanolixizumab 50mg/kg, 150mg/kg and control groups, respectively. Based on eNormograms for groups of 18 or 20 animals, these results were considered to be within the range of spontaneous prenatal losses naturally observed in cynomolgus monkeys. Foetal examinations revealed no treatment-related effects. All infants had normal postnatal development, although higher mortality was observed in female infants from the control group during the first 3 weeks. All infants were able to mount a normal immune response to keyhole limpet haemocyanin when vaccinated at the age of 4 months. Offspring from 150mg/kg-treated mothers had very low IgG levels at birth, indicating blockade of maternal IgG transfer; infants from mothers who received 50mg/kg had variable IgG levels at birth, with mothers who had developed significant anti-drug antibodies conferring maternal IgG transfer to varying degrees. Rates of infection in infants were similar across treatment groups. IgG levels in infants from rozanolixizumab-treated groups normalised within 2 months. Treatment of pregnant cynomolgus monkeys with the FcRn inhibitor rozanolixizumab had no adverse effects on pre- or postnatal development of offspring, including immune system development.

Development of a recombinant human IgG1 monoclonal antibody against the TRBV5-1 segment of the T cell receptor for the treatment of mature T cell neoplasms.

Mature T-cell neoplasms arise from the neoplastic transformation of a single T lymphocyte, and all cells in a neoplastic clone share the same V segment in the beta chain of the T-cell receptor (TCR). These segments may represent an innovative target for the development of targeted therapies. A specific V segment of the TCR beta chain (TRBV5-1) was analyzed using bioinformatic tools, identifying three potential antigenic peptides. One of these peptides, selected for synthesis, was used to screen a library of human single-chain variable fragments (scFv) through phage display. One fragment demonstrated high affinity and specificity for the antigen and was used to produce a human monoclonal antibody of the IgG1 class. Surface plasmon resonance (SPR) studies confirmed the high affinity of the monoclonal antibody for the antigen in the nanomolar range. Flow cytometry analysis on patients' samples demonstrated that the antibody, conjugated with a fluorochrome, selectively binds to tumor T lymphocytes expressing TRBV5-1, without binding to other lymphocytes or blood cell components. The development of fully human IgG1 monoclonal antibodies targeting specific V segments of the TCR beta chain represents a potential therapeutic option for patients with mature T-cell neoplasms.

Binding of therapeutic Fc-fused factor VIII to the neonatal Fc receptor at neutral pH associates with poor half-life extension.

Fusion of therapeutic proteins to the Fc fragment of human IgG1 promotes their FcRn-mediated recycling and subsequent extension in circulating half-life. However, different Fc-fused proteins, as well as antibodies with different variable domains but identical Fc, may differ in terms of extension in half-life. Here we compared the binding behaviour to FcRn of Fc-fused FVIII, Fc-fused FIX and two human monoclonal HIV-1 broadly-neutralizing IgG1, m66.6 and VRC01 with identical Fc. While all molecules bound FcRn at acidic pH, only rFVIIIFc and m66.6 interacted with FcRn at neutral pH. In silico modelling predicted a role for charged residues in the C1 and C2 domains of FVIII, and in the variable domains of m66.6, in the neutral binding to FcRn. Accordingly, mutations of key positively charged amino-acids in the FVIII C1C2 domains decreased the binding of the protein to FcRn at pH 7.4 in vitro and increased the half-life of rFVIIIFc in VWFKO mice. Our findings suggest that the removal of positively charged patches on Fc-fused proteins to ameliorate FcRn recycling without affecting therapeutic efficacy, may improve their pharmacokinetic properties.

P53 Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signalling

Abstract IL-23 is implicated in the pathogenesis of psoriasis (PsO), and myeloid cells expressing FcγRI (CD64) are the primary source of IL-23 in lesional PsO skin tissue. The incidence and prevalence of psoriatic arthritis increases with PsO severity, and joint disease activity is positively correlated with frequency of peripheral CD64+ monocytes. We evaluated: CD64 and IL-23 expression in PsO patient skin biopsies; binding of anti-IL-23p19 subunit IgG1 monoclonal antibodies (mAbs) guselkumab [(GUS) fully human, native Fc-region] and risankizumab [(RZB) humanized, mutated Fc-region] to CD64; and functional consequences of CD64 binding by anti-IL-23p19 subunit mAbs in in vitro assays. CD64, IL-23p19 and IL-23p40 subunits mRNA transcripts were analysed from bulk and single-cell RNAseq datasets. Binding of mAbs to IFNγ-primed human monocytes and IL-23–secreting inflammatory monocytes, and capture of endogenously secreted IL-23, were evaluated by flow cytometry. Internalization of IL-23 and GUS/RZB within CD64+ macrophages was assessed with live-cell confocal imaging. GUS and RZB potency for inhibiting IL-23 was determined in a co-culture of THP-1 cells (CD64+ monocyte cell line activated to produce IL-23) and an IL-23 reporter cell line (measuring biologically active IL-23). IL-23p19 mRNA transcript expression in the co-culture was measured by qPCR. Expression of CD64, IL-23p19, and IL-23p40 mRNA transcripts was increased in lesional vs. non-lesional PsO skin, as were the abundance of myeloid cell types co-expressing CD64/IL-23p19 mRNA transcripts. In in vitro assays, GUS (not RZB) demonstrated Fc-mediated binding to CD64 on IFNγ-primed monocytes. Moreover, CD64-bound GUS simultaneously captured IL-23 secreted from the same cells. GUS (not RZB) bound to the CD64+ macrophages and mediated IL-23 internalization to low pH intracellular compartments. GUS and RZB equipotently inhibited signalling by IL-23 present in THP-1-conditioned medium. However, in a co-culture of IL-23–producing THP-1 cells with an IL-23–responsive reporter cell line, GUS demonstrated enhanced potency vs. RZB for inhibiting IL-23 signalling. GUS did not alter IL-23p19 mRNA transcript expression in the co-culture. These findings were consistent with previous observations of CD64+ myeloid cells as a key source of IL-23 in lesional PsO skin tissue. GUS binding to CD64 on IL-23-producing cells likely contributed to the enhanced potency of GUS vs. RZB in inhibiting IL-23 signalling in the co-culture assay. These in-vitro data support a hypothesis for optimal localization of GUS in inflamed tissues, where CD64+ IL-23-producing myeloid cells are increased and in proximity to IL-23-responsive lymphoid cells, enhancing GUS neutralization of IL-23 at its source of production.

P130 ORKA-001: a novel extended half-life monoclonal antibody targeting IL-23 with the potential to improve upon currently available therapies for psoriasis

Abstract Introduction &amp; Objectives Interleukin 23 (IL-23) is a proinflammatory cytokine that helps to maintain and activate T-helper 17 (Th17) cells, the primary pathogenic cells in psoriasis. Antagonism of the p19 subunit of IL-23 (IL-23p19) has proven to have robust efficacy and a favourable safety profile in the treatment of psoriasis. ORKA-001 is a novel, extended half-life, humanized IgG1 monoclonal antibody that binds IL-23p19. ORKA-001 has been engineered to have optimized properties with the aim of delivering an enhanced clinical profile compared with current treatments for psoriasis. Materials &amp; Methods ORKA-001 was evaluated in multiple in vitro and ex vivo assays in comparison to two benchmark antibodies that target IL-23p19: risankizumab (RIS) and guselkumab (GUS). Binding affinity to IL-23 was determined by surface plasmon resonance (SPR). Antagonism of human IL-23 signalling was evaluated via assays measuring STAT3 activity in cell lines. Inhibition of IL-23-induced IL-17 secretion was assessed using in vitro cellular assays, including in human peripheral blood mononuclear cells (PBMC). Half-life extension was measured via pharmacokinetic (PK) analysis in cynomolgus monkeys dosed with a single bolus of ORKA-001. Results ORKA-001 binds specifically to human IL-23 with an affinity below 20 pM. It potently inhibits STAT3 activity in cell lines and IL-17 secretion in IL-23-stimulated human PBMC. IL-23 binding affinity and functional potencies for IL-23 antagonism are comparable to or better than those of RIS and GUS. The half-life of ORKA-001 is significantly extended in cynomolgus monkeys compared with both RIS and GUS. Based on allometric scaling of the clearance of ORKA-001 observed in this study, predictive simulations of ORKA-001 PK in humans suggest that subcutaneous maintenance dosing every 6–12 months could be achieved while maintaining high antibody exposures. Conclusion ORKA-001 exhibits high selectivity and affinity for IL-23 in vitro, potent inhibition of downstream cellular signalling ex vivo, and an extended half-life in non-human primates compared with RIS and GUS. Both affinity and antibody exposure have been shown to have a positive correlation with efficacy in psoriasis, and ORKA-001 has the potential to exceed RIS and GUS on both metrics while requiring significantly fewer doses per year. In total, these data provide preclinical evidence of ORKA-001’s clinical potential to improve upon currently available therapies for psoriasis. Clinical studies are warranted to demonstrate this potential.

P14 A multicentre, randomized, double-blind, placebo-controlled Phase II study to evaluate the efficacy and safety of individual dose regimens of HB0017 in patients with moderate-to-severe plaque psoriasis

Abstract HB0017 is a recombinant humanized IgG1 monoclonal antibody that targets IL-17A. To investigate HB0017 optimal dosage and possible dosing interval during maintenance therapy to inform Phase III studies. A total of 81 patients with moderate-to-severe plaque psoriasis received HB0017 300 mg (n = 41) or placebo (n = 40) at Weeks 0, 1, 2, 4, and 8. From Week 12 to Week 28, patients in the HB0017 group were given HB0017 300 mg once every 8 weeks. And patients in the placebo group were given HB0017 300 mg at Week 12, 13, 14 and 16, and then every 4 weeks until Week 28. Efficacy, safety, pharmacokinetics, and immunogenicity were assessed in Week 36. After 12 weeks of treatment, HB0017 300 mg resulted in significantly higher PASI 90 and sPGA0/1 response rates vs. placebo (P &amp;lt; 0.001). At Week 12, in the HB0017 group, 69.4% of patients achieved PASI 90, increasing to 97.6% at Week 24, then maintained throughout the follow-up period. And 78.2% of patients achieved sPGA0/1, increased to comparable peak levels at Week 28(97.6%), then maintained to Week 36(97.5%). In the placebo group, 1.0% of patients achieved PASI 90 at Week 12, increased to 94.3% at Week 28, then maintained throughout the follow-up period. 1.1% of patients achieved sPGA0/1, increased to 91.2% at Week 24, then maintained to Week 36(91.4%). The overall safety profile of HB0017 was similar to those of similar drugs, and no new safety signals were identified. These data provide evidence to support the evaluation of HB0017 300 mg maintenance dosing both every 8 and every 4 weeks in Phase III clinical trials.

Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 versus reference denosumab in healthy males: A randomized phase I study.

Denosumab is a human IgG2 monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) for the treatment of osteoporosis and bone loss. HLX14 is a proposed biosimilar of denosumab. This randomized, parallel-group, two-part, phase I study aimed to compare the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 with reference denosumab in Chinese healthy adult male participants. In Part 1, participants were randomized 1:1 and given HLX14 or reference denosumab sourced from the European Union (EU). In double-blind Part 2, participants were randomized 1:1:1:1 to receive HLX14 or denosumab sourced from the United States, EU, or China. All study drugs were administered via subcutaneous injection at a single dose of 60 mg. The primary endpoints were area under the serum drug concentration-time curve from time 0 to the last concentration-quantifiable time t (AUC0-t), maximum serum drug concentration (Cmax), and area under the serum drug concentration-time curve from time 0 to infinity (AUC0-inf). Twenty-four participants were randomized in Part 1 and 228 in Part 2. The 90% confidence intervals of geometric mean ratio of AUC0-t, Cmax, and AUC0-inf between HLX14 and denosumab from different sources fell within the pre-specified similarity margins of 0.80-1.25 (AUC0-t, 0.91-1.13; Cmax, 0.91-1.13; AUC0-inf, 0.91-1.12), demonstrating pharmacokinetic similarity. No notable difference was observed among treatment groups in pharmacodynamics, safety, or immunogenicity. HLX14 demonstrated highly similar pharmacokinetic characteristics with comparable pharmacodynamics, safety, and immunogenicity to denosumab, supporting its further investigation as a potential denosumab biosimilar.

Ibalizumab’s Role in Multidrug-Resistant HIV

Although treatment for HIV has advanced considerably over the decades, there are still people with HIV that is resistant to multiple antiretroviral therapies (ART). Ibalizumab, a humanized IgG4 monoclonal antibody that gained orphan status in 2018, is a post-attachment inhibitor whose efficacy for people with multidrug-resistant (MDR) HIV has been demonstrated in Phase II and III trials. The Prospective and Retrospective Observational Study of Multidrug-Resistant Patient Outcomes with and without Ibalizumab in a Real-World Setting: United States (PROMISE-US) is an ongoing study that will investigate long-term efficacy and durability of ibalizumab plus an optimized background regimen (OBR). In the poster discussed here, presented at IDWeek 2024, examination of baseline demographics showed that individuals prescribed ibalizumab (IBA group) had similar mean age, sex, race, and duration since diagnosis of HIV to those on regimens that did not include ibalizumab (non-IBA group). However, mean baseline HIV RNA copies/mL were much higher and CD4+ T cells/mm3 lower in the IBA group compared with the non-IBA group, and highest/lowest at baseline in a subset of IBA group patients who were also prescribed the capsid inhibitor lenacapavir. OBR also differed between groups. These results highlight the HIV-related characteristics of individuals who are more likely to be prescribed ibalizumab.

Anti-tumor activity and biomarker analysis for TROP2-antibody drug conjugate Datopotamab deruxtecan in patient-derived breast cancer xenograft models.

Datopotamab deruxtecan (Dato-DXd), is a humanized anti-TROP2 IgG1 monoclonal antibody linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCXs) varying in TROP2 expression. The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors post-neoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines. Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival (EFS) in 8 (73%) models while IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged EFS in 3 (27%) models. TROP2 RNA and protein was significantly higher in Dato-DXd-sensitive models. In isogenic cell lines derived from Dato-DXd-resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the 2 Dato-DXd-sensitive BCXs but not in a Dato-DXd-resistant BCX. In Dato-DXd-sensitive models, antitumor activity was enhanced in combination with PARP inhibitor, olaparib. Dato-DXd is active in breast cancer models. Dato-DXd has TROP2 dependent and independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.