Theranostic targeting of CUB domain containing protein 1 (CDCP1) in multiple subtypes of bladder cancer

Purpose: Despite recent approvals for checkpoint inhibitors and antibody drug conjugates targeting NECTIN4 or TROP2, metastatic bladder Cancer (BC) remains incurable and new treatment strategies are urgently needed. CUB domain containing protein 1 (CDCP1) is a cell surface protein and promising drug target for many cancers. This study aimed to determine whether CDCP1 is expressed in BC and whether CDCP1 can be targeted for treatment with radiolabeled Antibodies.

Experimental design: CDCP1 expression was evaluated in four BC datasets (n = 1,047 biopsies). A tissue microarray of primary BC biopsies was probed for CDCP1 by immunohistochemistry. CDCP1 expression was evaluated in patient derived xenografts and cell lysates. Tumor detection in mouse BC models was tested using 89Zr-labeled 4A06, a monoclonal antibody targeting the ectodomain of CDCP1. 177Lu-4A06 was applied to mice bearing UMUC3 or HT1376 xenografts to evaluate antitumor effects (CDCP1 expression in UMUC3 is 10 fold higher than HT1376).

Results: CDCP1 was highest in the basal/squamous subtype, and CDCP1 was expressed in 53% of primary biopsies. CDCP1 was not correlated with pathologic or tumor stage, metastatic site, or NECTIN4 and TROP2 at the mRNA or protein level. CDCP1 ranged from 105 - 106 receptors per cell. Mechanism studies showed that Ras signaling induced CDCP1 expression. 89Zr-4A06 PET detected five human bladder Cancer xenografts. 177Lu-4A06 inhibited the growth of UMUC3 and HT1376 xenografts.

Conclusions: These data establish that CDCP1 is expressed in BC, including TROP2 and NECTIN4-null disease, and suggest that BC can be treated with CDCP1-targeted radiotherapy.