Clinical and biological effects of an agonist anti-CD40 antibody: a Cancer Research UK phase I study

Clin Cancer Res. 2015 Mar 15;21(6):1321-8. doi: 10.1158/1078-0432.CCR-14-2355. Epub 2015 Jan 14.


Purpose: 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.

Trial registration: NCT01561911.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal / therapeutic use
  • Antigen-Presenting Cells / immunology
  • Antineoplastic Agents / therapeutic use
  • B-Lymphocytes / immunology*
  • CD40 Antigens / antagonists & inhibitors*
  • CD40 Antigens / biosynthesis
  • CD40 Antigens / immunology
  • Chemokine CCL4 / blood
  • Female
  • Humans
  • Immunoglobulin G / adverse effects
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Immunoglobulin G / therapeutic use*
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Interleukin-12 Subunit p35 / blood
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Activation / immunology
  • Lymphocyte Count
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Receptors, Complement 3d / biosynthesis
  • T-Lymphocytes / immunology*
  • Transaminases / metabolism


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • CD40 Antigens
  • Chemokine CCL4
  • ChiLob7-4 antibody
  • IL12A protein, human
  • Immunoglobulin G
  • Interleukin-12 Subunit p35
  • Receptors, Complement 3d
  • Intercellular Adhesion Molecule-1
  • Transaminases

Associated data