Abstract 1084: Preclinical testing of a cell adhesion molecule 1 (CADM1) targeting antibody-drug conjugate in osteosarcoma and other pediatric solid tumor models
Authors: Zhongting Zhang, Yifei Wang, Wendong Zhang, Xiangjun Tian, Qi Wang, Rossana N Lazcano Segura, Michael Roth, Jonathan Gill, Douglas Harrison, Zhaohui Xu, Yianhua Yi, Sylvester Jusu, Giuseppe Longo, Xin Zhou, Jing Wang, Richard Gorlick
Journal: Cancer Research (2024)

Abstract Introduction: Survival outcomes of osteosarcoma have remained stagnant for decades, emphasizing the urgent need to identify new cell surface targets and develop novel therapies. Antibody-drug conjugates (ADCs), known for their targeted delivery of cytotoxic agents to specific targets, present an attractive therapeutic class for potential use in osteosarcoma. Methods: We previously identified Cell Adhesion Molecule 1 (CADM1) is highly expressed on the cell surface in osteosarcoma using an integrated proteomic and transcriptomic surfaceome profiling approach. As a proof of concept, a humanized CADM1 antibody (clone PTA021-A1) was conjugated with Tesirine (SG3249), a pyrrolobenzodiazepine (PBD) dimer payload. The antitumor activity of this CADM1 ADC was validated in vivo in 8 osteosarcoma patient-derived xenografts (PDXs). CADM1 is also highly expressed in other pediatric solid malignancies such as neuroblastoma and Wilms tumor. The CADM1 ADC was tested in vitro in neuroblastoma and Wilms tumor models. Negative controls included a CD19 targeting ADC with the same payloads and CADM1 negative Ewing sarcoma models. Results: The expression of the CADM1 was validated by flow cytometry in osteosarcoma, neuroblastoma, and Wilms tumor cell lines, and by immunohistochemistry (IHC) in osteosarcoma patient samples and PDX models. In vivo testing of CADM1 ADC in 8 osteosarcoma PDX models showed that the ADC was well-tolerated and significantly prolonged progressive-free survival in all osteosarcoma models. Complete response (CR) and maintained CR was observed in 3 models. In vitro testing for neuroblastoma and Wilms tumor is ongoing, and preliminary data suggest promising antitumor activities. Conclusions: CADM1 is highly expressed in osteosarcoma and other pediatric solid tumors. CADM1 ADC demonstrated promising antitumor in vitro and in vivo activity in osteosarcoma, and initial in vitro studies in neuroblastoma and Wilms tumor show similarly promising responses. These data support the need for further studies assessing the potential of a CADM1 ADC as a novel agent for the treatment of pediatric solid cancers. Citation Format: Zhongting Zhang, Yifei Wang, Wendong Zhang, Xiangjun Tian, Qi Wang, Rossana N Lazcano Segura, Michael Roth, Jonathan Gill, Douglas Harrison, Zhaohui Xu, Yianhua Yi, Sylvester Jusu, Giuseppe Longo, Xin Zhou, Jing Wang, Richard Gorlick. Preclinical testing of a cell adhesion molecule 1 (CADM1) targeting antibody-drug conjugate in osteosarcoma and other pediatric solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1084.