A Phase I Clinical Research Study Evaluating the Safety, Tolerability and Biological Effects of the Chimeric Anti-CD40 Monoclonal Antibody Chi Lob 7/4 Given Intravenously, Weekly for Four Weeks in the Treatment of Patients With Advanced Malignancies Refractory to Conventional Anti-cancer Treatment.

The Purpose of this study is to evaluate the safety and tolerability, and the biological effects of the chimeric anti-CD40 monoclonal antibody Chi Lob 7/4, given intravenously, weekly for 4 weeks in the treatment of patients with advanced malignancies refractory to conventional anti-cancer treatment.

开始日期2007-07-01

申办/合作机构

Cancer Research UK

100 项与 Anti-CD40 ChiLob7/4(BioNTech SE) 相关的临床结果

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100 项与 Anti-CD40 ChiLob7/4(BioNTech SE) 相关的转化医学

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100 项与 Anti-CD40 ChiLob7/4(BioNTech SE) 相关的专利（医药）

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项与 Anti-CD40 ChiLob7/4(BioNTech SE) 相关的文献（医药）

2022-07-29·Science Immunology

Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility

Article

作者: Wagner, Armin ; Chan, Claude H.-T. ; Glennie, Martin J. ; White, Ann L. ; Inzhelevskaya, Tatyana ; Mockridge, Ian ; Elliott, Isabel ; Tews, Ivo ; Pearson, Arwen R. ; Orr, Christian M. ; Fisher, Hayden ; Cragg, Mark S. ; Yu, Xiaojie ; Booth, Steven G. ; Penfold, Christine A. ; Gao, Yunyun ; Essex, Jonathan W. ; Duriez, Patrick J.

Antibodies protect from infection, underpin successful vaccines and elicit therapeutic responses in otherwise untreatable cancers and autoimmune conditions. The human IgG2 isotype displays a unique capacity to undergo disulfide shuffling in the hinge region, leading to modulation of its ability to drive target receptor signaling (agonism) in a variety of important immune receptors, through hitherto unexplained molecular mechanisms. To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40. We report how agonistic activity varies with disulfide pattern and is afforded by the presence of a disulfide crossover between F(ab) arms in the agonistic forms, independently of epitope, as observed in the determined crystallographic structures. This structural “switch” affects directly on antibody conformation and flexibility. Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics.

2015-03-15·Clinical Cancer Research1区 · 医学

Clinical and Biological Effects of an Agonist Anti-CD40 Antibody: A Cancer Research UK Phase I Study

1区 · 医学

Article

作者: Steven, Neil ; Ottensmeier, Christian ; Geldart, Tom ; Challis, Ruth ; Johnson, Peter ; Edwards, Ceri ; Smith, Anna ; Williams, Anthony ; Tutt, Alison ; Chowdhury, Ferdousi ; Kerr, Paul ; Hodges, Elisabeth ; Chan, Claude ; Glennie, Martin ; Harvey, Melanie ; Ashton-Key, Margaret ; Gao, Yifang

AbstractPurpose: This phase I study aimed to establish the biologic effects and MTD of the agonistic IgG1 chimeric anti-CD40 antibody ChiLob7/4 in patients (pts) with a range of CD40-expressing solid tumors and diffuse large B-cell lymphoma, resistant to conventional therapy. Potential mechanisms of action for agonistic anti-CD40 include direct cytotoxic effects on tumor cells and conditioning of antigen-presenting cells.Experimental Design: ChiLob7/4 was given by IV infusion weekly for 4 doses at a range from 0.5 to 240 mg/dose. Validated ELISAs were used to quantify ChiLob7/4 in serum and test for anti-chimeric MAb (HACA) responses. Pharmacodynamic assessments included quantitation of T-cell, natural killer–cell, and B-cell numbers and activation in blood by flow cytometry and a panel of cytokines in plasma by Luminex technology. Planned dose escalation was in cohorts of 3 patients until MTD or biologic effect, defined as reduction of peripheral blood CD19+ B cells to 10% or less of baseline.Results: Twenty-nine courses of treatment were given to 28 subjects. The MTD was 200 mg × 4, with dose-limiting toxicity of liver transaminase elevations at 240 mg. At 200 mg (range between 2.1 mg/kg and 3.3 mg/kg based on patient body weight), the trough level pretreatment was above 25 μg/mL. Grade 1-2 infusion reactions were seen above the dose of 16 mg, but could be prevented with single-dose corticosteroid premedication. HACA responses were seen after doses between 1.6 mg and 50 mg, but not above this. There were dose-dependent falls in blood B-cell numbers accompanied by reduced expression of CD21, and transient reductions in NK cell numbers with increased CD54 expression from 50 mg upward. MIP-1β and IL12 plasma concentrations rose after doses above 16 mg. Fifteen of 29 treatments were accompanied by disease stabilization for a median 6 months, the longest for 37 months.Conclusions: ChiLob7/4 can activate B and NK cells at doses that can be administered safely, and should be tested in combination with other antibodies and chemotherapy agents. Clin Cancer Res; 21(6); 1321–8. ©2015 AACR.

2014-03-01·Cancer Immunology Research1区 · 医学

Ex Vivo Assays of Dendritic Cell Activation and Cytokine Profiles as Predictors of In Vivo Effects in an Anti-Human CD40 Monoclonal Antibody ChiLob 7/4 Phase I Trial

1区 · 医学

Article

作者: Williams, A.P. ; Glennie, M.J. ; Chowdhury, F. ; Johnson, P.W.

AbstractImmunostimulatory antibodies entering the clinic create challenge in terms of not only pharmacodynamics for monitoring anticipated mechanisms but also predetermining cytotoxicity. We show the use of ex vivo whole-blood samples to predict the activation requirements, cytokine signature, and adverse events of an anti-human-CD40 chimeric IgG1 antibody, ChiLob 7/4. Assessments were initially undertaken on human myeloid (mDC1) and plasmacytoid (pDC) dendritic cells, in which an absolute need for cross-linking was shown through the upregulation of activation markers CD83 and CCR7. Subsequent cytokine secretion evaluations of ex vivo whole blood showed the cross-linked antibody-induced increases in MIP1β, interleukin (IL)-8, IL-12, TNFα, and IL-6. This cytokine signature compared favorably with the Toll-like receptor (TLR) ligand lipopolysaccharide (LPS), in which levels of TNFα and IL-6 were significantly higher, suggesting a less intense proinflammatory response and possible modified cytokine release syndrome when used in human trials. Following first-in-human use of this agent within a dose escalation study, in vivo evaluations of dendritic cell activation and secreted cytokines closely matched the predetermined immunomonitoring endpoints. Patients showed a comparable pattern of MIP1β, IL-8, and IL-12 secretion, but no TNFα and IL-6 were identified. Mild symptoms relating to a cytokine release syndrome were seen at an equivalent dosage to that observed for dendritic cell activation and cytokine release. In summary, ChiLob 7/4 induces a distinctive pattern of dendritic cell activation and cytokine secretion in ex vivo assays that can be predictive of in vivo responses. Such preclinical approaches to monoclonal antibody evaluation may inform both the starting dosages and the anticipated cytokine release events that could occur, providing a valuable adjunct for future first-in-human assessments of immunostimulatory antibodies. Cancer Immunol Res; 2(3); 229–40. ©2013 AACR.

100 项与 Anti-CD40 ChiLob7/4(BioNTech SE) 相关的药物交易

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