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First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies

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  • Sandra M M Irenaeus
  • Dorte Nielsen
  • Peter Ellmark
  • Jeffrey Yachnin
  • Adnan Deronic
  • Anneli Nilsson
  • Per Norlén
  • Niina Veitonmäki
  • Camilla S Wennersten
  • Gustav J Ullenhag
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Agonistic CD40 antibodies activate dendritic cells and can expand and activate tumor-specific T cells. Our purpose was to assess the CD40 agonistic antibody ADC-1013 in the clinical setting including intratumoral administration since preclinical studies have indicated that intratumoral is better than intravenous administration. A Phase I, open label, multicenter study was conducted in patients with advanced solid tumors who had received established treatments. A modified 3 + 3 dose-escalation was applied (every other week dosing). Twenty-three patients were treated with ADC-1013 intratumorally (dosing from 22.5 μg/kg up to 400 μg/kg) or intravenously (dosing at 75 μg/kg). The pharmacodynamic effects observed in the patients were further verified in an hCD40tg mouse model. Adverse events were mostly Common Terminology Criteria for Adverse Events (CTCAE) Grades 1 or 2 and transient. The serum concentration ADC-1013 and cytokine release (MCP-1, TNFα and IL-6) were more pronounced in patients receiving injections in deep metastases compared to patients receiving injections in superficial metastases. Treatment with ADC-1013 resulted in a marked decrease in B cell levels in peripheral blood after 24 h while remaining B cells significantly increased their expression of the cell surface activation marker CD86. Activation of antigen-presenting cells and subsequent activation of T cells were demonstrated in hCD40tg mice. Moreover, ADC-1013 treatment in this mouse model acted synergistically with a PD-1 inhibitor. The results from the first-in-human study of ADC-1013 indicate that intratumoral administration of ADC-1013 into superficial lesions is well tolerated at clinically relevant doses and associated with pharmacodynamic responses.

Original languageEnglish
JournalInternational Journal of Cancer
Volume145
Issue number5
Pages (from-to)1189-1199
Number of pages11
ISSN0020-7136
DOIs
Publication statusPublished - 1 Sep 2019

    Research areas

  • Adult, Aged, Animals, Antibodies, Monoclonal, Humanized/administration & dosage, B-Lymphocytes/drug effects, Cell Line, Tumor, Dose-Response Relationship, Drug, Female, Humans, Infusions, Intralesional, Infusions, Intravenous, Macaca fascicularis, Male, Melanoma, Experimental/drug therapy, Mice, Middle Aged, Neoplasms/drug therapy, Young Adult

ID: 59280750