Docetaxel‐Induced Immune Activation Shows Antitumor Synergy With the Tumor‐Targeted CD40 Agonist KK2269

ABSTRACT Tumor‐targeted CD40 agonists have emerged as one of the novel strategies to activate intratumoral antigen‐presenting cells (APCs), subsequently inducing T‐cell‐specific antitumor responses. However, their clinical efficacy as monotherapy has been limited, highlighting the need for effective combination therapies. We developed KK2269, a bispecific antibody targeting epithelial cell adhesion molecule (EpCAM) on tumor cells and CD40 on APCs, designed to selectively activate APCs in the presence of EpCAM‐positive tumors. Our studies demonstrated that KK2269 activates APCs only in the presence of EpCAM‐expressing cells. Using the immunologically cold B16F10‐mouse EpCAM subcutaneously transplanted model, the antitumor effects of KK2269 in combination with clinically approved drugs, including anti‐programmed cell death 1 (PD‐1) antibody, docetaxel, doxorubicin, oxaliplatin, and gemcitabine were evaluated. KK2269 showed significant antitumor activity in combination with an anti‐PD‐1 antibody, docetaxel, doxorubicin, or oxaliplatin, but not gemcitabine, with docetaxel showing the most significant antitumor effect(s). Intratumoral immune analysis showed that KK2269 was associated with increased expression of APC activation markers, whereas docetaxel was associated with increased expression of dendritic cell (DC)‐related genes. Moreover, expression of APC and T‐cell activation markers was higher with docetaxel+KK2269 than with either monotherapy. The antitumor and immune activation effects of docetaxel+KK2269 were also observed in the immunosuppressive intrahepatic transplantation model. This study provides a rationale for combining a tumor‐targeting CD40 agonist, KK2269, with docetaxel for the treatment of PD‐1 blockade resistant tumors, including intrahepatic tumors, and supports exploration of this combination strategy in the clinic.