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

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 2 nd 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 profiles 1,2, 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 vitro 2 . 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). 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 (7_Supplement): 6297 3. AACR; Cancer Res 2021;81(13_Suppl): Abstract nr 1832 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 19.47 a RT112/84 Maximum kill (%) 93.6 94.3 a Bladder FGFR3 fusions RT4 IC50 (nM) 1.10 68.76 a RT4 Maximum kill (%) 83.5 53.7 a Bladder FGFR3 fusions SW-780 IC50 (nM) 0.26 61.76 a SW-780 Maximum kill (%) 87.0 61.9 a Lung Kras G12V NCI-H441 IC50 (nM) 0.43 13.12 b NCI-H441 Maximum kill (%) 69.8 56.4 b 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 3.06 c HCC 1954 Maximum kill (%) 80.2 52.5 c 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 11.8 c