Abstract 1580: HuB14-VA-PL2202, a novel antibody-drug conjugate targeting ASCT2, a novel ADC target over-expressed in both solid and hematological cancers

Abstract SLC1A5 (Solute Carrier family 1 member 5), also known as ASCT2 (Alanine, Serine, Cysteine Transporter 2), is a Na+ dependent antiporter with its preferred substrate being glutamine. ASCT2 expression is reported in normal tissues, however it has been shown to be dramatically increased in several solid tumors (lung, colorectal) and hematological malignancies (acute myeloid leukemia (AML), multiple myeloma). Moreover, high ASCT2 expression was associated with a worse prognosis in liver and lung cancers. Because of this profile of expression, ASCT2 is an appealing membrane protein for pharmacological targeting. We have developed a new antibody-drug conjugate (ADC) targeting ASCT2 (HuB14-VA-PL2202), composed of a humanized IgG1 directed against human ASCT2, to which PL2202, consisting of a proprietary cleavable linker and exatecan, a topoisomerase I inhibitor, has been site-specifically conjugated with a drug to antibody ratio ∼6. FcγR-mediated effector function was abrogated via mutation in the Fc portion of the antibody. The aim of this study was to characterize the in vitro cytotoxicity of HuB14-VA-PL2202 in human cancer cell lines, and determine its in vivo efficacy. The safety and tolerability of HuB14-VA-PL2202 was also evaluated in cynomolgus monkeys. Membrane expression of ASCT2 was confirmed by IHC in sections from xenograft biopsies and human tissues.In vitro, HuB14-VA-PL2202 was readily internalized by ASCT2+ve cancer cells, showed specific binding to CHO cells expressing recombinant human or cynomolgus monkey ASCT2, and displayed potent cytotoxic activity in a range of target positive cancer cell lines, both from solid and hematological tumors. In vivo, HuB14-VA-PL2202 dosed once at 6 mg/kg was able to significantly delay tumor growth in the subcutaneous (sc) G-402 human renal leiomyoblastoma cancer xenograft model. Likewise, in the sc MOLM-13 AML xenograft model, HuB14-VA-PL2202 dosed once at 10 mg/kg achieved 5/10 tumor free survivors at the end of the study. In a PK study in human FcRn Tg32 SCID mice, HuB14-VA exhibited a 7.4 day half-life; whilst in a DRF study in cynomolgus monkeys, HuB14-VA-PL2202 was tolerated at 40 mg/kg, indicating there is a favorable therapeutic index. Membrane expression of ASCT2 was confirmed by IHC, in sections of xenograft models and tissue microarray (TMA) of human cancer indications. ASCT2 expression in NSCLC and HNSCC was found to be significantly higher than in the correspondent normal tissue. In conclusion, ASCT2 represents an interesting novel tumor target for an ADC approach. HuB14-VA-PL2202 demonstrated potent and specific in vitro cytotoxicity and in vivo anti-tumor activity in both hematological and solid tumor models, and was well tolerated in cynomolgus monkeys. Together, the data generated with HuB14-VA-PL2202 warrants its further development into the clinic in cancers over-expressing ASCT2. Citation Format: Danilo Cucchi, Elizabeth Horsley, Alina Chrzastek, Ben Leatherdale, Simone Sims, Nicole Bledowski, Banusha Rajeenthira, Narinder Janghra, Lara Montolio, Abigail Kimpalu, Christopher Gallagher, Charlie Britten, Lolke de Haan, Paul W. Hogg, Chris Pickford, Patrick H. van Berkel. HuB14-VA-PL2202, a novel antibody-drug conjugate targeting ASCT2, a novel ADC target over-expressed in both solid and hematological cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1580.