A Chemically Defined Trifunctional Antibody–Cytokine–Drug Conjugate with Potent Antitumor Activity

Abstract

The combination of immunostimulatory agents with cytotoxic drugs is emerging as a promising approach for potentially curative tumor therapy, but advances in this field are hindered by the requirement of testing individual combination partners as single agents in dedicated clinical studies, often with suboptimal efficacy. Here, we describe for the first time a novel multipayload class of targeted drugs, the immunocytokine-drug conjugates (IDC), which combine a tumor-homing antibody, a cytotoxic drug, and a proinflammatory cytokine in the same molecular entity. In particular, the IL2 cytokine and the disulfide-linked maytansinoid DM1 microtubular inhibitor could be coupled to the F8 antibody, directed against the alternatively spliced EDA domain of fibronectin, in a site-specific manner, yielding a chemically defined product with selective tumorhoming performance and potent anticancer activity in vivo, as tested in two different immunocompetent mouse models.

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

“…It has recently been shown that certain cytotoxic agents can mediate an immunogenic tumor cell death [44,45]. In addition, certain immunostimulatory agents (e.g., antibody-cytokine fusion proteins, immunological check-point inhibitors) may potently synergize with some cytotoxic agents [46][47][48].…”

Emerging formats for next-generation antibody drug conjugates

“…The synergistic behaviour was thought to be due to dying cells having increased immune-stimulatory power. This is called an IDC (immunocytokine drug conjugate) but the IC 50 s need to be matched as the dose can only be achieved by a single molecule [103]. This format was exceptionally potent at around 0.5 mg/kg in an F9 teratocarcinoma model.…”

Identification of important long non-coding RNAs and highly recurrent aberrant alternative splicing events in hepatocellular carcinoma through integrative analysis of multiple RNA-Seq datasets

“…A high-affinity human anti-ED-A monoclonal antibody F8 has been generated targeting tumor neovasculature in vivo (Villa et al 2008). Based on antibody F8 several potent anti-cancer biopharmaceuticals have been developed such as immunocytokines F8-IL13 (Hess and Neri 2015) and F8-IL2 (Pretto et al 2014) and immunocytokine drug conjugate F8-IL2-SS-DM1 (List et al 2014). On the other hand, splicing of FN1 towards producing the isoform with CS1 exon was up-regulated in isoform percentage in the majority of HCC samples.…”