CDCP1: A New Therapeutic Target for Malignant Tumors

The invasion and metastasis of malignant tumors are key research areas in oncology.  Among all prevalent targets, CUB Domain-Containing Protein 1, or CDCP1, emerges as a promising new target with high expression levels in multiple cancer malignancies, playing a critical role in cancer cell survival and proliferation, cancer metastasis, as well as drug resistance [1].

Structure and Function of CDCP1

CDCP1, also known as CD318, gp140, SIMA135, or Trask [2], is a type I transmembrane protein with a molecular weight of ~135 kDa. Full-length CDCP1 (fl-CDCP1) consists of three extracellular CUB-like domains and 14 N-glycosylation sites, as well as five intracellular tyrosine phosphorylation sites. In normal tissues, the expression of fl-CDCP1 is restricted [3], but it is significantly upregulated in various malignant tumors such as metastatic triple-negative breast cancer (TNBC), metastatic HER2-positive breast cancer, lung adenocarcinoma, colorectal cancer, prostate cancer, pancreatic ductal adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC) [1].

Schematic diagram of fl-CDCP1 protein [1]

In tumor cells, elevated protease levels in the tumor microenvironment induce cleavage of fl-CDCP1 by serine proteases such as plasmin, trypsin, and uPA, producing cleaved CDCP1 (c-CDCP1). This yields a ~65 kDa N-terminal fragment (CDCP1-NTF) and a ~70 kDa membrane-bound, C-terminal fragment (CDCP1-CTF) [4], with cleavage mainly occurring between residues R368 and K369. The resulting CTF is later recognized and phosphorylated by SRC family kinases, especially at tyrosine 734 (Y734). Phosphorylated CTF recruits PKCδ and subsequently activates downstream MAPK and PI3K/AKT signaling pathways [1]. CTF can also form homodimers or heterodimers with other membrane proteins like β1-integrin, enhancing signal transduction and integrating extracellular matrix (ECM) signals to promote cell migration and invasion [1].

For the NTF fragment, it remains controversial whether it detaches from or remains on the cell surface after cleavage. Some studies show that ATF can be shed from the surface of various prostate cancer cell lines and be detected in the serum of colorectal cancer patients [3]; while others report that ATF remains bound to the cell surface and tightly associates with CTF [5].

Strategies for Antibody Development Targeting CDCP1

Given the distinct structural forms of CDCP1 under pathological conditions, antibody drug development primarily follows two strategies:

1. Targeting fl-CDCP1 — to directly inhibit its expression or block proteolytic cleavage.

2. Targeting c-CDCP1 or CTF — to specifically recognize new epitopes exposed after cleavage, thereby precisely blocking oncogenic downstream signaling.

During immunization and screening, different antigen formats such as fl-CDCP1, CTF&ATF, or CTF&ATF connected by a long linker can be used. Importantly, the β-sheet interactions between ATF and CTF are critical for proper CTF folding and thus, the CTF alone cannot be expressed independently in vitro [5]. Therefore, to generate CTF-specific antibodies, one strategy is to immunize with full-length CDCP1, then perform negative selection with ATF, allowing the screening of antibodies that specifically recognize CTF.

Proteolysis of CDCP1 [1]

Currently, no CDCP1-targeted drugs have been approved globally. In June 2025, Huiyu Pharmaceutical’s HY0001a received IND clearance for clinical trials, the world’s first disclosed CDCP1-targeting program reached the clinic.  HY0001a is an antibody-drug conjugate (ADC) developed for advanced solid tumors. It arrests proliferating tumor cells at the G2/M phase and significantly induces apoptosis in the MDA-MB-231 CDX tumor model [6].

In addition, there are several ADCs targeting CDCP1 in preclinical development.

• InduPro’s IDP-001, the first bispecific ADC targeting EGFR×CDCP1, recognizes EGFR domain III and the distal membrane region of CDCP1 [7]. It shows potent tumor-killing activity across multiple models and is expected to file for IND in Q1 2026 [8].

• ch10D7-MMAE by University of Queensland,  targets fl-CDCP1-ATF (aa 30–358), causing CDCP1 internalization and demonstrating strong anti-tumor activity in xenograft models of pancreatic, colorectal, and ovarian cancers [3].

ch10D7 antibody targeting fl-CDCP1 [3]

UCSF’s monoclonal antibody CL-03 targets a novel c-CDCP1 epitope near the C-terminus of ATF. CL-03 specifically kills tumor cells expressing c-CDCP1 with no toxicity to normal cells [5]. 

CL-03 monoclonal antibody targeting c-CDCP1 [6]

Selected CDCP1-targeting drugs

High-Quality CDCP1 Proteins Supplied by KACTUS

Given the unique structural forms of CDCP1 under pathological conditions, choosing suitable antigen formats is crucial during drug development. As the research interest in CDCP1 continues to grow, KACTUS has, based on structural insights, designed and developed various CDCP1 protein formats including fl-CDCP1, ATF&CTF, and the ATF domain, covering multiple species and suitable for diverse applications, facilitating improved antibody discovery against distinct epitopes

Product Data

Immobilized Human CDCP1 at 2 µg/ml (100 µl/well). Dose-response curve for Anti-CDCP1 Antibody (hFc Tag) with an EC₅₀ of 5.4 ng/ml determined by ELISA (QC Test).

Immobilized Human CDCP1 ATF&CTF (fused by polypeptide linker), His Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-CDCP1 Antibody, hFc Tag with the EC50 of 4.2 ng/ml determined by ELISA (QC Test).

Immobilized Human CDCP1 ATF&CTF (co-transfected complex), His Tag at 2 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-CDCP1 Antibody, hFc Tag with the EC50 of 17.1 ng/ml determined by ELISA (QC Test).

The purity of Human Human CDCP1 ATF&CTF (co-transfected complex) is greater than 90%. The molecular weight of this protein is around 80-101 kDa as determined by SEC-MALS, which is similar to that of fl-CDCP1 (QC Test).

Immobilized Human CDCP1 ATF (30-368), His Tag at 2 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-CDCP1 Antibody, hFc Tag with the EC50 of 4.6 ng/ml determined by ELISA (QC Test).

Product List

References

1. Khan T. et al. The CDCP1 Signaling Hub: A Target for Cancer Detection and Therapeutic Intervention. Cancer Research, 81(9), 2259–2269 (2021).

2. Donahue K.L. & Pasca di Magliano M. Cleaved CDCP1 marks the spot: a neoepitope for RAS-driven cancers. J. Clin. Invest., 132(4): e157168 (2022).

3. Khan T. et al. CUB Domain-Containing Protein 1 (CDCP1) is a rational target for the development of imaging tracers and antibody-drug conjugates for cancer detection and therapy. Theranostics, 12(16): 6915–6930 (2022).

4. Hanahan D. & Weinberg R.A. Hallmarks of Cancer: The Next Generation. Cell, 144(5): 646–674 (2011).

5. Lim S.A. et al. Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers. J. Clin. Invest., 132(4): e154604 (2022).

6. Abstract 4256: HY0001a: A novel ADC targeting CDCP1. Cancer Research, AACR.

7. Abstract 5445: Discovery and optimization of IDP-001, a bispecific ADC targeting EGFR and CDCP1. Cancer Research, AACR.

8. Pipeline - InduPro.