Abstract 1202: Targeting cell adhesion molecule 1 (CADM1) with an antibody drug conjugate for the treatment of osteosarcoma

Introduction: Survival outcomes for patients with osteosarcoma have been stagnant for decades. There is an urgent need to identify new surface targets in osteosarcoma and develop novel therapies to increase cure rates. Antibody-drug conjugates, due to their targeted delivery of cytotoxic payloads to specific targets, are an attractive class of agents for potential use in osteosarcoma. Methods: We used an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma but minimally expressed on normal tissues. Cell-surface expression of the identified target antigen was validated by IHC and flow cytometry in osteosarcoma cell lines, patient-derived xenograft (PDX) models, and a patient tumor tissue microarray. As a proof of concept, humanized CADM1 antibody (clone PTA021-A1) was conjugated with tesirine (SG3249), a pyrrolobenzodiazepine (PBD) dimer payload. The antitumor activity of this antibody-drug conjugate was tested in vitro and in vivo in osteosarcoma cell lines and PDX models. Results: Cell Adhesion Molecule 1 (CADM1) was found to be enriched in osteosarcoma at both protein and mRNA levels, while minimally expressed in normal tissues. Flow cytometry validated the cell-surface localization and expression levels of CADM1 in 7 osteosarcoma cell lines. We performed immunohistochemistry (IHC) staining using an osteosarcoma tissue microarray from 37 patients and 19 PDX models. CADM1 was expressed in 100% of the patient samples and PDXs. The newly developed ADC induced cytotoxic effects in 100% (5/5) of osteosarcoma cell lines, with IC 50 at 120h ranging from 0.009 to 0.1 ug/ml. In vivo testing is ongoing. Preliminary data shows objective response and prolonged survival in selected osteosarcoma PDX models. The mice tolerated the ADC well with minimal toxicity. Conclusions: CADM1 is highly expressed in most osteosarcoma samples and minimally expressed in normal human tissue, which makes it an attractive target for respective antigen-targeting ADC therapies. The CADM1 targeting ADC showed antitumor activities in osteosarcoma preclinical models which may warrant further investigation of CADM1 targeted therapies for osteosarcoma. Acknowledgments: This work was funded by Swim Across America, the Foster Foundation, the Osteosarcoma Institute Translational and Preclinical Grant, and the Barbara Epstein Foundation. Citation Format: Yifei Wang, Zhongting Zhang, Wendong Zhang, Xiangjun