Abstract 3179: Rationale for the development of a differentiated Trop2 ADC in solid tumors of the bladder, lung, and breast

Abstract Background: Trop2 is a transmembrane protein that is overexpressed in several solid tumor cancers and is a validated target. Trop2 ADCs are approved in TNBC, Her2- HR+ metastatic breast cancer, and 2nd line EGFR-mutated NSCLC in US, China, or Japan. PH1 is a unique immunomodulatory payload targeting the spliceosome and has been used as a platform to generate a Trop2 PH1 ADC and other pipeline ADCs with differentiated preclinical efficacy and safety profiles1, 2, 3. Following significant characterization and derisking of the Akari Trop2 ADC program, the clinical candidate, AKTX-101, is progressing for IND-enabling studies. Results: Previously, a 75-cell line screen was performed and Trop2 PH1 ADC demonstrated single digit nanomolar (nM) IC50 potency in 8 solid tumor indications in vitro2. In follow-up experiments, AKTX-101 was tested alongside first-in-class approved Trop2 ADCs and compared with Standard-of-care targeted therapy in these models to identify an advantageous niche for the clinical development of AKTX-101 (Table 1 Table 1: AKTX-101 vs SOC, where a=Enfortumab vedotin, b= Daraxonrasib, c=Trastuzumab deruxtecan Indication Driver mutation Cell line Metric AKTX-101 Standard of care Bladder FGFR3 fusions RT112/84 IC50 (nM) 0. 30 19. 47a RT112/84 Maximum kill (%) 93. 6 94. 3a Bladder FGFR3 fusions RT4 IC50 (nM) 1. 10 68. 76a RT4 Maximum kill (%) 83. 5 53. 7a Bladder FGFR3 fusions SW-780 IC50 (nM) 0. 26 61. 76a SW-780 Maximum kill (%) 87. 0 61. 9a Lung Kras G12V NCI-H441 IC50 (nM) 0. 43 13. 12b NCI-H441 Maximum kill (%) 69. 8 56. 4b Lung BRAF G466V NCI-H1666 IC50 (nM) 0. 07 NCI-H1666 Maximum kill (%) 90. 0 Lung SMARCA4 deletion NCI-H2126 IC50 (nM) 0. 43 NCI-H2126 Maximum kill (%) 75. 1 Breast Different sensitivity to Top1 agents, Her2 amplification HCC 1954 IC50 (nM) 0. 39 3. 06c HCC 1954 Maximum kill (%) 80. 2 52. 5c Breast Trastuzumab resistant, Her2 amplification, HR- negative, PIK3CA, TP53 mutations JIMT-1 IC50 (nM) 0. 35 N. A. c JIMT-1 Maximum kill (%) 89. 6 11. 8c). As AKTX-101 exhibited nM IC50 potency in all urothelial models tested (5/5), and since the PH1 payload is known to synergize with anti-PD-1, the ADC was tested plus/ minus checkpoint inhibitor in a syngeneic MB49 mouse model of urothelial cancer overexpressing human Trop2. Sequential dosing of ADC followed by mPD-1 demonstrated synergy whereas concomitant dosing was associated with additive anti-tumor efficacy. Conclusion: Our results support the clinical development of AKTX-101 in bladder cancer and in other solid tumor niches. These niches will be explored further in planned translational studies. References: 1. Mitra SK. 951 A novel splicing-targeted ADC payload drives immune activation, synergy with checkpoint inhibitors, and enhanced therapeutic potential beyond cytotoxicity. Journal for ImmunoTherapy of Cancer. 2025; 13: . 2. Cancer Res (2023) 83 (7Supplement): 6297 3. AACR; Cancer Res 2021;81 (13Suppl): Abstract nr 1832 Citation Format: Satyajit K. Mitra, Mastewal Abuhay, Mary Do. Rationale for the development of a differentiated Trop2 ADC in solid tumors of the bladder, lung, and breast 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 3179.