Selected Articles from This Issue

Trophoblast cell surface antigen 2 (TROP2) is a promising target for cancer therapy. Here, Li and colleagues present the preclinical evaluation of OBI-992, a TROP2-targeted antibody-drug conjugate (ADC). OBI-992 is composed of a novel TROP2 antibody conjugated to a topoisomerase I inhibitor exatecan via a hydrophilic linker. OBI-992 showed potent antitumor activity with strong bystander killing effect in various cancer models. In a xenograft model overexpressing P-glycoprotein or breast cancer resistant protein, OBI-992 retained its robust antitumor activity when benchmark ADCs became less effective. The results support the clinical development of OBI-992 in patients with advanced solid tumors (NCT06480240).Administration of IL-12 systemically has demonstrated limited efficacy and notable side effects, emphasizing the necessity for innovation. To address these concerns, Lee and colleagues developed a FAP-targeted IL12mut fusion protein, FAP-IL-12mut TMEkine—a novel immunotherapeutic agent which incorporated specific IL-12 mutations. FAP-IL-12mut was engineered to target FAP-expressing cells in preclinical cancer models. FAP-IL-12mut not only modified the TME by increasing immune cell infiltration, thereby augmenting anti-tumor immune responses, but also reduced cytotoxicity events in this study, relative to targetless or wild-type IL-12. These results suggest that the development of selective targeting and alleviated activity are crucial for IL-12 therapy and supports the consideration of FAP-IL-12mut in clinical trials for the treatment of solid tumors with FAP-expressing TME.Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) has a critical dependency on nicotinamide adenine dinucleotide (NAD), a redox cofactor produced by the biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). Here, Najera and colleagues defined NAMPT inhibition as a potential therapeutic approach for FH-deficient HLRCC-associated renal cell carcinoma. The results of this study uncover a novel druggable target in FH-deficient renal tumors that shows promise as a single agent in preclinical models and could be further explored in combination with other agents and in other tumors characterized by this metabolic shift to aerobic glycolysis.Tissue factor (TF) is a transmembrane protein that undergoes rapid internalization once bound by an antibody, making it a suitable target for antibody drug conjugates (ADCs). TF overexpression is associated with cancer development and poor prognosis. Here, Kantak and colleagues describe XB002, an anti-TF ADC designed to selectively deliver a cytotoxic payload to TF-expressing tumors, while minimizing TF-related adverse events. Preclinical studies of XB002 showed potent antitumor activity in multiple TF-expressing solid tumor models with encouraging safety and no significant impact on coagulation, supporting the feasibility of this approach for cancer therapy.