title: Clinical and biological effects of an agonist anti-CD40 antibody: a Cancer Research UK phase I study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom. NIHR/CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom. johnsonp@soton.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Johnson
authors.affiliation: NIHR/CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Challis
authors.affiliation: NIHR/CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Ferdousi
authors.initials: F
authors.lastname: Chowdhury
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Harvey
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Geldart
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Kerr
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Claude
authors.initials: C
authors.lastname: Chan
authors.affiliation: NIHR/CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Smith
authors.affiliation: NIHR/CRUK Experimental Cancer Medicine Centre, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Steven
authors.affiliation: Drug Development Office, Cancer Research UK, London, United Kingdom.
authors.forename: Ceri
authors.initials: C
authors.lastname: Edwards
authors.affiliation: NIHR/CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashton-Key
authors.affiliation: NIHR/CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hodges
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Tutt
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom. NIHR/CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Ottensmeier
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom. NIHR/CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Glennie
authors.affiliation: Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom. NIHR/CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Williams
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000938:Antigen-Presenting Cells / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D054407:Chemokine CCL4 / Q000097:blood; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000097:blood / Q000276:immunology / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D053765:Interleukin-12 Subunit p35 / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D018655:Lymphocyte Count; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017464:Receptors, Complement 3d / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology*; D000637:Transaminases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D054407:Chemokine CCL4; C000604564:ChiLob7-4 antibody; C508858:IL12A protein, human; D007074:Immunoglobulin G; D053765:Interleukin-12 Subunit p35; D017464:Receptors, Complement 3d; D018799:Intercellular Adhesion Molecule-1; D000637:Transaminases