DuoBody®-FAPαxDR4 is a novel DR4 agonist that induces potent antitumor activity through FAPα-dependent, DR4-transactivation-mediated apoptosis
Jamila Laoukili, Ilse Jongerius, Bart E.C.G. de Goeij, Madelon Paauwe, Edouard Souteyrand, Susanne van Schelven, Grietje Andringa, André Verheem, Anne van de Loo, Monique N.H. Luijten, Saskia D. van Asten, Edo D.R. Elstak, Theo S. Plantinga, David Satijn, Esther C.W. Breij, Onno Kranenburg, Marije B. OverdijkAbstract
Purpose Death receptor (DR) agonism is a promising strategy for cancer treatment, but clinical success has been limited by insufficient efficacy and/or on-target off-tumor toxicity, particularly hepatotoxicity. We hypothesized that restricting DR4 activation to the tumor microenvironment may enhance both therapeutic efficacy and safety. Fibroblast activation protein alpha (FAPα) is overexpressed on cancer-associated fibroblasts (CAFs) within the tumor stroma of several solid cancers, making it an attractive target for conditional activation of DR4 on tumor cells. Experimental Design DuoBody-FAPαxDR4 is an Fc-silenced IgG1 bispecific antibody that binds to DR4 on tumor cells and FAPα on CAFs. Functional activity of DuoBody-FAPαxDR4 was assessed in tumor cell lines and colorectal carcinoma (CRC) patient-derived organoids (PDOs) using viability and bioluminescent reporter assays. Toxicity was tested using human primary liver spheroids in vitro. In vivo, antitumor activity was evaluated in patient-derived xenograft (PDX) models and models for spontaneous multiorgan metastasis by implantation of CRC-derived organoids into the cecum. Results DuoBody-FAPαxDR4 localized to the fibroblast-tumor cell interface, where it induced conditional caspase-8 activation and cytotoxicity in DR4-expressing tumor cells while sparing the fibroblasts. DuoBody-FAPαxDR4 did not induce cytotoxicity in human primary liver spheroids. In vivo, DuoBody-FAPαxDR4 demonstrated potent antitumor activity in PDX models and in mouse models of multiorgan metastases of CRC. Conclusions DuoBody-FAPαxDR4 is a novel bispecific antibody that conditionally activates DR4 on cancer cells exclusively in the presence of FAPα-expressing cells, resulting in targeted apoptosis and antitumor activity. These findings supported the initiation of a first-in-human trial in patients with solid tumors.