Abstract Purpose: HER2 is overexpressed in 15-20% of breast cancers and some other cancers, and the development of HER2-targeted therapies has revolutionized cancer treatment in past 20 years. Trastuzumab (Tr) has demonstrated efficacy in treatment of HER2+ breast cancer and advanced gastric cancer. Recently, Tr-based antibody drug conjugates (ADCs), Kadecyla and Enhertu, have emerged as a new class of anti-HER2 therapies by combining targeted antibodies with cytotoxic agents via linkers. However, ADC approach faces great challenges, such as in vivo instability, manufacturing processes, limited availability of antitumor payloads and suboptimal payload release. Therefore, smarter and more efficient designs are urgently needed. Methods: Our patented single protein encapsulation (SPE) platform, allowing encapsulation of small-molecule drugs by a single protein (albumins or globulins) without artificial nanoparticles and chemical modifications to drugs and proteins, has achieved great success in development of 2 drug products, SPEDOX-6 under human clinical trial (NCT0764018) and SPESN38-8 (IND #: 164346) under IND-enabling study based on albumin, which have prompted us to utilize antibody, such as Tr to encapsulate cytotoxic payload, actinomycin D (ACT, RNA polymerase inhibitor), forming antibody encapsulated drugs (AEDs). We developed Tr-ACT2 as a first-in-class AED drug, featuring each Tr molecule to encapsulate two ACT molecules without linkers. Tr-ACT2 was well characterized by UV, fluorescence, membrane dialysis, particle size distribution and molecular docking. In vitro and in vivo anticancer efficacy of Tr-ACT2 against various HER2+ Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1667.
Yu et al. (Fri,) studied this question.