Abstract B068: <i>In vitro</i> and <i>in vivo</i> efficacy of the antibody-drug-conjugate (ADC) PB-vcMMAE-5 against human ovarian cancer expressing truncated core 2 O-glycans

Abstract Introduction: Ovarian cancers remain largely unresponsive to immune checkpoint inhibitors, in part due to their ability to suppress the cytotoxic activity of immune cells infiltrating the tumor microenvironment. One of the disrupted pathways in these cancers is O-glycosylation, a feature, particularly associated with ovarian cancer progression, metastasis and poor prognosis. This underscores the urgent need for alternative immunotherapeutic strategies. The monoclonal antibody (mAb) PB-223 was developed through affinity maturation of NEO-102, a chimeric human IgG1 mAb that targets tumor specific truncated core-2 O-glycans. PB-223 exhibits 4-fold improvement in binding affinity (KD) compared to NEO-102 and recognizes a boarder range of tumor tissues while sparing normal tissue. We developed an ADC, designated PB-vcMMAE-5, composed of the mAb PB-223 conjugated via the mc-vc-PABc linker to the microtubule-inhibitor MMAE. PB-vcMMAE-5 has a drug-to-antibody ratio of 3.92 and demonstrates stability in human plasma. This study aimed to evaluate the therapeutic efficacy of PB-vcMMAE-5 both in vitro and in vivo in ovarian cancer models. Experimental Design: In this study, the in vitro cytotoxicity of PB-vc-MMAE-5 was assessed in 4 human cancer cell lines, including triple negative breast (HCC1937, MDA-MB-231), ER+, PR+, HER2+ breast (BT474), and ovarian (OV-90). Cells were treated with various ADC concentrations for 5 days, and cytotoxicity was quantified using a luminescence assay. In vivo efficacy was evaluated in NOD-SCID mice bearing OV-90 xenografts, mice were treated once weekly for 5 weeks with PBS, payload alone or PB-vcMMAE-5 at doses 1, 3, 6 and 9 mg/kg (n = 6 per group). Tumor growth inhibition (TGI), % changes in tumor volume, body weight, hematology and clinical chemistry parameters were monitored. Results: PB-vcMMAE-5 induced significant cytotoxicity across all tested cell lines, whereas naked PB-223 showed no cytotoxicity. In vivo, on day 1, the mean tumor volume across all six groups was approximately 116.5 mm3. PB-vcMMAE-5, at 3, 6 and 9 mg/kg resulted in substantial TGI of 94.14%, 109.06% and 109.24% respectively, on day 21 post-treatment. The mean tumor volume changes (%) on day 21 for the PBS control, payload alone and PB-vcMMAE-5 at doses 1, 3, 6 and 9 mg/kg were +969.82, +669.72, +817.80, +64.95, -73.47 and -68.43 respectively. Treatment with payload alone or PB-vcMMAE-5 at 1mg/kg did not significantly reduce tumor volume compared to the PBS control. No significant changes in body weight were observed in any treatment groups. Conclusions: PB-vc-MMAE-5 exhibited anti-ovarian cancer activity both in vitro and in vivo, with good tolerability. Additional dosing on day 28, as well as hematology and chemistry assessments, are ongoing. These findings support the potential of PB-vc-MMAE-5 as a therapeutic candidate for ovarian tumors expressing truncated core 2 O-glycans. Citation Format: Kwong Tsang, Massimo Fantini, Anjum Zaki, Sharon A. Mavroukakis, Christine M. Annunziata, Philip M. Arlen. In vitro and in vivo efficacy of the antibody-drug-conjugate (ADC) PB-vcMMAE-5 against human ovarian cancer expressing truncated core 2 O-glycans [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B068.