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

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.