Data from HPN328, a Trispecific T Cell–Activating Protein Construct Targeting DLL3-Expressing Solid Tumors

• DOI: 10.1158/1535-7163.c.7431527.v1
• Publication Date: 2024-09-04T08:42:23Z
• Authors: Mary E. Molloy; Wade H. Aaron; Manasi Barath; Mabel C. Bush; Evan C. Callihan; Kevin Carlin; Michael Cremin; Thomas Evans; Maria G. Guerrero; Golzar Hemmati; Avneel S. Hundal; Llewelyn Lao; Payton Laurie; Bryan D. Lemon; S.J. Lin; Jessica O’Rear; Purbasa Patnaik; Sony Sotelo Rocha; Linda Santiago; Kathryn L. Strobel; Laura B. Valenzuela; Chi-Heng Wu; Stephen Yu; Timothy Z. Yu; Banmeet S. Anand; Che-Leung Law; Liping L. Sun; Holger Wesche; Richard J. Austin

<div>Abstract<p>Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC highly aggressive, limited therapeutic options lead to poor prognosis for patients. HPN328 a trispecific T cell–activating construct (TriTAC) consisting three binding domains: CD3 binder T-cell engagement, an albumin half-life extension, DLL3 engagement. <i>In vitro</i> assays, rodent models, non-human primates were used assess the activity HPN328. induces potent dose-dependent killing DLL3-expressing lines <i>in vitro</i>, concomitant with activation cytokine release. In NCI-H82 xenograft model established tumors, treatment led recruitment anti-tumor activity. immunocompetent mouse expressing human CD3ε epitope, mice previously treated withstood rechallenge, demonstrating long-term immunity. When repeat doses administered cynomolgus monkeys, was well tolerated up 10 mg/kg. Pharmacodynamic changes, such as transient elevation, observed, consistent expected mechanism action engagers. exhibited linear pharmacokinetics given dose range serum 78 187 hours, supporting weekly or less frequent administration humans. Preclinical nonclinical characterization suggests that efficacious, safe, novel candidate. A phase 1/2 clinical trial currently underway testing safety efficacy patients malignancies.</p></div>