Double-Blinded, Randomized, Placebo-Controlled, Single Ascending Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BMS-986090 in Healthy Subjects

The purpose of this study is to evaluate the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-986090 in healthy subjects.

开始日期2014-05-01

申办/合作机构

Bristol Myers Squibb Co.

100 项与 BMS-986090 相关的临床结果

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100 项与 BMS-986090 相关的转化医学

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100 项与 BMS-986090 相关的专利（医药）

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项与 BMS-986090 相关的文献（医药）

2025-06-01·Arthritis & Rheumatology

Outcome of Patients With Lupus Nephritis Treated With an Anti‐CD40 Monoclonal Antibody According to Kidney Biopsy Features

Article

作者: Simone Deutschel ; Martina Uzzo ; Helmut Schumacher ; Ingeborg Bajema ; Juergen Steffgen ; David Jayne

Objective:

A phase 2 trial tested different doses of the anti‐CD40 monoclonal antibody BI 655064 as an add‐on therapy to the standard of care in patients with class III or IV lupus nephritis (LN) with active disease. A post hoc analysis showed a potential benefit of the higher tested doses (180 and 240 mg) versus a low dose (120 mg) or placebo. We investigated whether the treatment effect of BI 655064 on kidney outcomes may be modified by the presence of glomerular monocytes, a target for this drug with a well‐known role in LN pathogenesis.

Methods:

One hundred one renal biopsies of patients with LN enrolled in the BI 655064 trial were scored centrally. The estimated glomerular filtration rate (eGFR), spot urine protein/urine creatinine ratio (UP/UC), and complete renal response (CRR) were evaluated over 52 weeks. Patients were divided according to a “better” or “worse” performance than the average of all patients in the cohort, predicted by a mixed model for repeated measurements. Logistic regression models adjusted for potential confounders were used to assess the association between different treatment doses and outcomes according to the presence or absence of monocytes.

Results:

A higher BI 655064 dose (180 or 240 mg) was associated with better outcomes of UP/UC and CRR when glomerular monocytes were present in kidney biopsy samples (odds ratio [OR] 3.66 [95% confidence interval (CI) 1.09–12.3], P = 0.04; OR 4.58 [95% CI 1.24–16.9], P = 0.02). A trend toward improved eGFR was also observed in these patients (at 52 weeks, P = 0.08).

Conclusion:

In LN kidney biopsy samples with glomerular monocytes, high‐dose BI 655064 treatment improved proteinuria at 52 weeks and resulted in a higher CRR compared to biopsy samples without glomerular monocytes. Histologic features may guide the choice of treatment for individual patients with LN.image

2020-09-01·Veterinary ophthalmology4区 · 农林科学

Anti‐CD40 monoclonal antibody ameliorates experimental autoimmune uveoretinitis in mice

4区 · 农林科学

Article

作者: Pan, Yongquan ; Jin, Lei ; Tian, Na ; He, Mingzhong ; Chen, Feilan ; Xu, Lei ; Gao, Jie

Abstract:

Objective:

To investigate the effects of CD40 on ocular inflammation in experimental autoimmune uveoretinitis (EAU) in B10.RIII mice.

Animals studied:

EAU‐susceptible B10.RIII mice were subcutaneously immunized with interphotoreceptor retinoid‐binding protein (IRBP) 161‐180 in complete Freund's adjuvant and evaluated clinically and pathologically on days 7, 14, 21, 28, and 35 postimmunization. Anti‐CD40 antibody was intraperitoneally injected into mice every other day from days 7 to 14 postimmunization. Phosphate‐buffered saline (PBS)‐injected EAU mice were used as the controls.

Procedures:

The frequencies of CD11c+CD40+ dendritic cells (DCs), CD11c+MHC‐II+ DCs, and CD11c+CD40+MHC‐II+ DCs in splenocytes were evaluated by flow cytometry on days 0, 7, 14, and 21 after immunization. Tumor necrosis factor (TNF)‐α and interleukin (IL)‐6 production in CD11c+ DCs was assessed by ELISA. IRBP‐specific lymphocyte proliferation was assessed using a modified MTT cell proliferation assay.

Results:

The number of CD11c+CD40+ DCs, CD11c+MHC‐II+ DCs, and CD11c+CD40+MHC‐II+ DCs increased at the onset of EAU, peaked at the height of disease severity, and was sustained at a high level until day 21. Treatment with anti‐CD40 antibody significantly alleviated clinical and pathological activities related to EAU. Compared with the control mice, antibody‐treated EAU mice showed few CD11c+CD40+ DC and CD11c+CD40+MHC‐II+ DC frequencies in splenocytes. The anti‐CD40 antibody significantly suppressed IRBP‐specific lymphocyte proliferation and TNF‐α and IL‐6 production by DCs in EAU mice.

Conclusions:

The increased expression of CD40 and major histocompatibility complex (MHC) class II molecules in the splenocytes of EAU mice were correlated with inflammatory activity. Anti‐CD40 treatment can significantly attenuate EAU activity by inhibiting systemic IRBP‐specific immune responses.

2016-06-01·Cancer cell1区 · 医学

Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement

1区 · 医学

Article

作者: Li, Fubin ; Yamniuk, Aaron P ; Korman, Alan J ; Barnhart, Bryan C ; Dahan, Rony ; Ravetch, Jeffrey V

While engagement of the inhibitory Fcγ-receptor (FcγR) IIB is an absolute requirement for in vivo antitumor activity of agonistic mouse anti-CD40 monoclonal antibodies (mAbs), a similar requirement for human mAbs has been disputed. By using a mouse model humanized for its FcγRs and CD40, we revealed that FcγRIIB engagement is essential for the activity of human CD40 mAbs, while engagement of the activating FcγRIIA inhibits this activity. By engineering Fc variants with selective enhanced binding to FcγRIIB, but not to FcγRIIA, significantly improved antitumor immunity was observed. These findings highlight the necessity of optimizing the Fc domain for this class of therapeutic antibodies by using appropriate preclinical models that accurately reflect the unique affinities and cellular expression of human FcγR.

项与 BMS-986090 相关的新闻（医药）

2018-08-22

·BioSpace

AbbVie Exercises Option to Develop Argenx Immuno-Oncology Compound

Chicago-based AbbVie has exercised its exclusive license option to develop and commercialize Belgium-based Argenx’s ARGX-115. The compound is an antibody that targets novel immuno-oncology target glycoprotein A repetitions predominant (GARP). Chicago-based AbbVie has exercised its exclusive license option to develop and commercialize Belgium-based Argenx ’s ARGX-115. The compound is an antibody that targets novel immuno-oncology target glycoprotein A repetitions predominant (GARP). The original deal was inked in April 2016. With today’s announcement, AbbVie picks up a worldwide, exclusive license to develop and commercialize ARGX-115-based products. Argenx is eligible for various milestone payments up to $625 million in addition to tiered royalties on any commercial products. Argenx also has the rights to co-promote any ARGX-115-based products in Europe and the Swiss Economic Area. “We are very excited by AbbVie’s decision to exercise its option to license and develop ARGX-115, given its compelling track record in oncology,” said Tim Van Hauwermeiren, Argenx’s chief executive officer, in a statement. “We are proud of the work that this milestone represents for Argenx—both in efficiently advancing a premier Innovative Access Program candidate to clinical development and in facilitating wider recognition of the important research out of the de Duve Institute/Catholique University of Louvain around this first-in-class target.” ARGX-115 is currently in preclinical studies. The compound binds specifically to GARP, which is key in regulating production and release of active transforming growth factor beta (TGF-beta). The companies believe the compound can selectively limit the immunosuppressive activity of activated regulatory T-cells (Tregs). This results in stimulating the immune system to attack cancer cells. The compound was discovered under Argenx’s Innovative Access Program with the de Duve Institute/Université Catholique de Louvain and WELBIO . It was then licensed under a research and option deal in 2013. Hauwermeiren went on to say, “Our Innovative Access Program remains a strategic priority for us, capitalizing on the combined strengths of the Argenx antibody platform and the deep disease biology expertise at research institutions. We continue to seek out cutting-edge research and targets while advancing our current collaborations, all with the potential to broaden our pipeline and demonstrate our discipline as a strategic partner.” Pharmaphorum notes, “AbbVie is lagging behind rivals in the field of cancer immunotherapy. While Bristol-Myers Squibb and Merck & Co . have been marketing PD-1 checkpoint inhibitors for several years, AbbVie’s PD-1 drug is only in early trials. AbbVie also has an anti-CD40 antibody in early stage development for solid tumors.” Eli Lilly is also working in the area of TGF-beta inhibition. Its galunisertib is in Phase II/III trials for hepatocellular carcinoma. “Immuno-oncology is one of AbbVie’s key focus areas in our mission to discover and develop medicines that drive transformational improvements in cancer treatment,” said Tom Hudson, AbbVie’s vice president, Oncology Early Discovery and Development, in a statement. “Our collaboration with Argenx over the past two years has been productive, and we look forward to continue working together to fuel scientific progress for patients.” According to Reuters, after the announcement, Argenx shares climbed by more than 6 percent in early trading. “After listing on the stock market in 2014, Argenx’s share price has increased tenfold and it joined Belgium’s blue-chip index Bel20 earlier this year.”

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