First Disclosures

CD47 is a cell surface glycoprotein that is expressed on normal human tissues and serves as a marker of self. Tumor cells have co-opted CD47 overexpression to evade immune surveillance, making blockade of CD47 an attractive strategy in oncology. However, clinical development of CD47-targeted agents has been complicated by its robust normal tissue expression. SGN-CD47M is a novel protease-activated anti-CD47 antibody that incorporates a functional IgG1 backbone whose binding and function is restricted to the tumor microenvironment. SGN-CD47M may have enhanced antitumor activity and improved tolerability relative to existing therapies that target CD47.

Pancreatic cancer is one of the most aggressive types of cancer with one of the lowest 5-year survival rates among all cancers. TROP2 is a promising therapeutic target in pancreatic cancer correlated with metastasis and poor prognosis. Here, Papacharisi and colleagues describe new TROP2 targeting ADCs containing the highly potent payload amanitin with a new mode of action with excellent antitumor efficacy in refractory pancreatic cancer and TNBC models. Taken together, the high in vivo efficacy, favorable PK profiles, and good tolerability supported a high therapeutic window, demonstrating the therapeutic potential of these novel TROP2 targeting ADCs for the treatment of pancreatic cancer.

KT-253 is a highly potent and selective heterobifunctional degrader of the MDM2 oncoprotein, a key E3 ligase that modulates the most common tumor suppressor, p53. While MDM2 small molecule inhibitors have been developed to stabilize and upregulate p53 expression, they have been found to induce a feedback loop that increases MDM2 levels, which can repress p53 and therefore limit their efficacy. In preclinical studies, Chutake and colleagues highlight the therapeutic potential of MDM2 degradation to overcome the MDM2 feedback loop, thereby robustly activating the p53 pathway and inducing apoptosis in a range of p53 wild-type hematologic and solid tumor models.

Androgen receptor (AR) signaling is a key driver of prostate cancer; AR pathway inhibitors are standard treatments for patients with this disease, but many tumors develop resistance, and patients experience disease progression. Here, Snyder and colleagues report preclinical evaluation of bavdegalutamide, a PROteolysis TArgeting Chimera (PROTAC) that harnesses the ubiquitin-proteasome system to induce AR degradation. Bavdegalutamide showed substantial AR degradation and tumor growth inhibition in prostate cancer animal models, including those with AR pathway inhibitor resistance. Bavdegalutamide, the first PROTAC to enter human clinical trials, was evaluated in a phase I/II study in patients with metastatic castration-resistant prostate cancer.

Glutathione S-Transferase P (GSTP) known as a Phase II detoxification enzyme has more recently been identified as a modulator of MAP kinase-related cell-signaling pathways. It is known to be upregulated in many cancers including KRAS-driven tumors such as NSCLC. Here, Cina and colleagues demonstrate how an siRNA-based therapeutic formulated in a lipid nanoparticle (NBF-006) that enhances delivery to tumors led to tumor regression in a dose dependent manner in multiple in vivo models. Preclinical studies supported the advancement of NBF-006 into clinical studies. This advancement may enable future development of RNA therapeutics for the treatment of cancers.

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).

IL-12 systemically demonstrated limited efficacy and notable side effects, emphasizing the necessity for innovation. To address these concerns, FAP-IL-12mut TMEkine™—a novel immunotherapeutic agent incorporated specific IL-12 mutations, called IL-12mut, which reduced toxicity. FAP-IL-12mut 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, compared with targetless or wild-type IL-12. These results suggest that the development of both targeting ability and alleviated activity is crucial for IL-12 therapy and supports the consideration of FAP-IL-12mut in clinical trials for treating solid tumors with FAP-expressing TME.

Most anti-PD1/PD-L1 antibodies have exhibited poor efficacy in some clinical indications, primarily due to insufficient infiltration of immune cells into the tumor microenvironment (TME). This study presents a novel biological mechanism for the design of an Fc-silenced anti-PD-L1/OX40 bispecific antibody (EMB-09), which aims to augment both peripheral and tumor-associated immune responses, thereby enhancing anti-tumor immunity. Through these mechanisms, EMB-09 has demonstrated superior anti-tumor activity compared to anti-PD-L1 monotherapy in preclinical animal models and has shown preliminary efficacy in early-phase clinical trials. The findings from this study could provide significant insights into cancer immunotherapy by modulating peripheral immune responses beyond the tumor microenvironment.

T cells in the tumor microenvironment require peptide-MHC–T Cell Receptor interaction (Signal 1) coupled with costimulatory receptor engagement (Signal 2) for optimal activation. Because tumors often lack natural costimulatory ligands, a tumor-specific Signal 1 in the absence of Signal 2 may be ineffective or even induce T cell anergy. Here, Moore and colleagues characterize the costimulatory properties of XmAb808, a B7-H3×CD28 bispecific antibody that conditionally activates T cells only in the presence of Signal 1 plus B7-H3-expressing tumor cells. XmAb808 stimulates efficient T cell-mediated cancer-cell killing in vitro and in humanized mouse models, supporting its clinical development as a solid-tumor immunotherapy.