Abstract 1289: ASP2998, a TROP2-targeted immunostimulatory antibody drug conjugate (iADC) with dual payloads, demonstrates potent efficacy and a favorable safety profile in nonclinical models

Abstract Objective: Trophoblast cell surface antigen-2 (TROP2) is a transmembrane glycoprotein implicated in various intracellular signaling pathways that promote cancer cell proliferation, migration, and invasion. TROP2 is frequently overexpressed across multiple tumor types. ASP2998 is a novel TROP2-directed immunostimulatory antibody drug conjugate (iADC) that incorporates two distinct payloads: a cytotoxic topoisomerase 1 inhibitor and an immunomodulator STING agonist. A series of nonclinical studies have been conducted to evaluate the nonclinical efficacy and safety of ASP2998. Methods: In vitro cytotoxicity, immune cell activation, and cytokine production were assessed using co-culture assays of TROP2-positive cancer cells and human peripheral blood mononuclear cells (PBMCs). Immune cell subsets (dendritic cells, CD4+ and CD8+ T cells, and NK cells) and cytokines (IL-6, IL-1β, TNFα, IFNγ, and IP-10) were analyzed. Tumor immune environment (TME) modulation was evaluated in mice bearing human TROP2-expressing MC38 (MC38-hTROP2) tumors. ASP2998 was administered intravenously and immune cell populations in tumors were analyzed by flow cytometry on Day 5. Primary antitumor efficacy and tumor rechallenge responses were compared between ASP2998 and a TROP2-directed toxin ADC, in a MC38-hTROP2 tumor model. A 4-week GLP-compliant toxicity study (QW x 4) was conducted in cynomolgus monkeys at ASP2988 doses of 3, 10, and 30 mg/kg/week. Results: ASP2998 exhibited potent cytotoxic activity against TROP2-positive cells and induced dose-dependent activation of human dendritic cells, CD4+ and CD8+ T cells, and NK cells, along with increased secretion of IL-6, IL-1β, TNFα, IFNγ, and IP-10. In vivo, ASP2998 at 1 mg/kg increased the frequency of total monocytes and activated (CD80+) monocytes and dendritic cells in tumors. It also significantly enhanced infiltration and activation (CD69+) of NK cells and increased the frequency of granzyme B+ NK and CD8+ T cells at both 0.3 and 1 mg/kg. ASP2998 surpassed the efficacy of a TROP2-directed toxin ADC against MC38-hTROP2 in vivo and provided greater protection against tumor rechallenge. ASP2998 demonstrated an acceptable safety profile in monkeys. Target organs included skin, cornea, kidney, urethra, trachea, and red blood cells. The highest non-severely toxic dose (HNSTD) was determined to be 10 mg/kg (QW x 4). Toxicokinetic profiles of the total antibody and ADCs were comparable, with minimal exposure to free payloads. Conclusion: ASP2998 is a first-in-class dual payload iADC that combines cytotoxic and immuno-stimulatory mechanisms to enhance antitumor efficacy and promote durable antitumor immunity while demonstrating a favorable safety profile in nonhuman primates. A first-in-human (FiH) clinical study is planned. Citation Format: Mark Orr, Takashi Chaen, Mai Shibata, Noritoshi Ishikawa, Toshihiro Matsuda, Yuji Fujita, Gillian Haggerty, Yuki Ochiai, Hiroaki Tanaka, Michinori Akaiwa, Xiaofan Li, Kshama A. Doshi, Wadie Mahauad-Fernandez, Krishna Bajjuri, Gang Yin. ASP2998, a TROP2-targeted immunostimulatory antibody drug conjugate (iADC) with dual payloads, demonstrates potent efficacy and a favorable safety profile in nonclinical models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1289.