Data from ATG-101 Is a Tetravalent PD-L1×4-1BB Bispecific Antibody That Stimulates Antitumor Immunity through PD-L1 Blockade and PD-L1–Directed 4-1BB Activation

• DOI: 10.1158/0008-5472.c.7234905.v1
• Publication Date: 2024-05-15T07:39:10Z
• Authors: Hui Yuwen; Huajing Wang; Tengteng Li; Yijing Ren; Yun-kai Zhang; Peng Chen; Ao Sun; Gang Bian; Bohua Li; David Flowers; Marc Presler; Kalyanasundaram S...; Jia Xue; Jingjing Wang; Kevin Lynch; Jay Mei; Xiaowen He; Bo Shan; Bing Hou
• Keywords: Bispecific antibody; Immune checkpoint

<div>Abstract<p>Immune checkpoint inhibitors (ICI) have transformed cancer treatment. However, only a minority of patients achieve profound response. Many are innately resistant while others acquire resistance to ICIs. Furthermore, hepatotoxicity and suboptimal efficacy hampered the clinical development agonists 4-1BB, promising immune-stimulating target. To effectively target 4-1BB treat diseases ICIs, we engineered ATG-101, tetravalent "2+2″ PD-L1×4-1BB bispecific antibody. ATG-101 bound PD-L1 concurrently, with greater affinity for PD-L1, potently activated 4-1BB<sup>+</sup> T cells when cross-linked PD-L1–positive cells. exhausted upon binding, indicating possible role in reversing T-cell dysfunction. displayed potent antitumor activity numerous <i>in vivo</i> tumor models, including those or refractory greatly increased proliferation CD8<sup>+</sup> cells, infiltration effector memory ratio T/regulatory microenvironment (TME), rendering an immunologically “cold” “hot.” Comprehensive characterization TME after treatment using single-cell RNA sequencing further revealed altered immune landscape that reflected immunity. was well tolerated did not induce non-human primates. According computational semimechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation receptor occupancy were both maximized at around 2 mg/kg providing guidance regarding optimal biological dose trials. In summary, by localizing PD-L1–rich microenvironments activating cross-linking–dependent manner, safely inhibits growth ICI tumors.</p>Significance:<p>The antibody activates minimizing existing suppressing ICI-resistant tumors.</p><p><i><a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-24-0566" target="_blank">See related commentary Ha et al., p. 1546</a></i></p></div>