Targeting CTF: A New Choice for CDCP1 Tumor Therapy

At the 2026 AACR Annual Meeting, the domestic biopharmaceutical company Biocytogen released the complete research data for its CDCP1-targeted ADC candidate, BCG046. CDCP1 is abnormally highly expressed in various solid tumors such as lung cancer, colorectal cancer, and pancreatic cancer, and is involved in regulating tumor proliferation, invasion, metastasis, and chemotherapy resistance processes. The extracellular domain of CDCP1 on the tumor cell membrane surface can be cleaved by proteases into a membrane-distal ATF fragment and a membrane-anchored, membrane-proximal CTF fragment; ATF carries the risk of shedding, and free ATF can neutralize antibodies targeting this region, weakening the drug's targeted killing effect. The complete structure of BCG046 consists of three parts: the fully human antibody Ab.168 targeting the membrane-proximal CTF domain of CDCP1, a Val-Cit (vc) cleavable linker, and the MMAE microtubule inhibitor toxin. Through directed screening, Ab.168 specifically binds only to CTF, mechanistically avoiding the efficacy loss caused by shed antigens. In vivo efficacy data show that in PDX models of non-small cell lung cancer and colorectal cancer, the anti-tumor activity of BCG046 is superior to or comparable with that of similar benchmark antibody-vcMMAE ADCs. Leveraging a differentiated CTF epitope layout, it opens a brand-new development direction for CDCP1-targeted therapy in solid tumors^[1]. 

BCG046 Poster^[1]

Structure and Function of CDCP1

CUB Domain-Containing Protein 1 (CDCP1), also known as CD318, gp140, SIMA135, and Trask^[2], with its full-length form denoted as fl-CDCP1, is a type I transmembrane protein with a molecular weight of 135 kD. Its extracellular segment contains 3 CUB-like domains and 14 N-glycosylation sites, while the intracellular segment contains 5 tyrosine phosphorylation sites. The expression of fl-CDCP1 is restricted in normal tissues^[3], but its expression 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, and non-small cell lung cancer^[4]. 

Schematic diagram of the fl-CDCP1 structure^[4]

In tumor cells, elevated protease levels in the tumor microenvironment induce the cleavage of fl-CDCP1 by serine proteases such as plasmin, matrix metalloproteinases, and uPA, generating cleaved CDCP1 (c-CDCP1). This results in an approximately 65 kD amino-terminal fragment (CDCP1-ATF) and an approximately 70 kD transmembrane carboxyl-terminal fragment (CDCP1-CTF)^[5], with the cleavage site primarily occurring between R368 and K369. The cleaved CTF can be recognized and phosphorylated by SRC family kinases, particularly at the tyrosine at position 734 (Y734). The phosphorylated CTF can recruit PKCδ, further activating downstream signaling pathways such as MAPK and PI3K/AKT. The cleaved CTF can undergo homodimerization or form heterodimers with other membrane proteins such as β1 integrin. This heterodimerization not only enhances signal transduction but also integrates extracellular matrix (ECM) signals to promote cell migration and invasion^[4]. 

Studies show that the cleavage-generated ATF can shed from the surface of multiple prostate cancer cell lines and has been detected in the serum of colorectal cancer patients^[3]. If an antibody targets ATF, the free antigen could neutralize the drug, potentially weakening the drug's anti-tumor killing activity; however, some studies also indicate that after cleavage, ATF remains on the cell surface and binds tightly to CTF^[6]. Based on the special structural forms of CDCP1 that may exist under pathological conditions, there are two main strategies for developing its antibody drugs: one is to specifically target CTF or the neoepitope formed after cleavage to precisely block its downstream pro-tumorigenic signal transduction; the other is to target fl-CDCP1 to directly disrupt its expression or block its cleavage. During the immunization and screening stages, different forms of antigen proteins can be used, such as CTF, CTF&ATF, CTF&ATF linked by a long linker, or fl-CDCP1. 

The proteolytic process of CDCP1^[4]

CDCP1 Drug Development Progress

IDP-001 is an EGFR×CDCP1 bispecific ADC developed by InduPro. Addressing the off-target toxicity and drug resistance flaws of single-target EGFR ADCs, this drug relies on the synergistic recognition mechanism of dual EGFR and CDCP1 antigens to achieve specific endocytotic killing only in double-positive tumor cells. In CDX models of colorectal cancer and non-small cell lung cancer, IDP-001 exhibited dose-dependent anti-tumor activity, with an in vivo half-life of approximately 16 hours in mice and good tolerability in all dose groups. Under identical dosing conditions, its tumor inhibitory effect was significantly superior to that of EGFR or CDCP1 single-target ADCs. In non-small cell lung cancer PDX models, 6 out of 8 double-positive tumor models achieved complete tumor regression after administration. Preclinical in vivo data fully validate that IDP-001 has broad-spectrum and potent anti-tumor potential, and the drug is currently undergoing Phase I/II clinical trials. 

Structure of IDP-001^[7]

Huiyu Pharmaceutical's HY0001a was approved for clinical trials in June 2025. It is the world's first disclosed clinical-stage project targeting CDCP1, indicated for advanced solid tumors, and is an ADC drug. HY0001a can arrest proliferating cancer cells in the G2/M phase and significantly induce apoptotic pathways in tumor tissues of the MDA-MB-231 CDX model^[8]. 

Besides the aforementioned BCG046, there are multiple ADC drugs in the preclinical stage. For instance, ch10D7-MMAE developed by the University of Queensland targets aa30-aa358 of the fl-CDCP1-ATF, blocking the cleavage of fl-CDCP1, and has shown potent anti-tumor effects in mouse xenograft models of pancreatic cancer, colorectal cancer, and ovarian cancer^[3]. 

10D7 antibody targeting fl-CDCP1^[3]

In terms of monoclonal antibodies, CL-03 developed by UCSF targets a neoepitope on c-CDCP1, binding near the C-terminus of ATF. CL-03 can specifically kill tumor cells expressing c-CDCP1 without exhibiting toxicity to healthy cells. 

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

Partial List of CDCP1-Targeted Drugs

KACTUS Supplies High-Quality CDCP1 CTF Domain Proteins

CDCP1 is an extremely promising hot target in the current solid tumor ADC space, with multiple targeted drugs having entered the clinical stage. Proteases in the tumor microenvironment cleave full-length CDCP1 to generate ATF and CTF; however, ATF carries the risk of shedding, which may neutralize antibodies and drastically weaken drug efficacy. Therefore, targeting CTF can be a differentiated strategy for CDCP1 drug development. Based on an understanding of the CDCP1 structure, KACTUS prominently launches its core featured product, the CDCP1 CTF domain protein, assisting clients in immunizing and screening for antibodies targeting CTF epitopes. Furthermore, we also supply different forms of antigen proteins such as the ATF&CTF complex, ATF domain, and fl-CDCP1, featuring rationally designed protein tags that do not mask crucial epitopes. These products cover multiple species and are suitable for various application scenarios. 

Product Data

Human CDCP1 CTF, hFc Tag immobilized on CM5 Chip can bind Anti-CDCP1 CTF Antibody1 with an affinity constant of 59.11 nM as determined in SPR assay (Biacore T200).

Human CDCP1 CTF, hFc Tag immobilized on CM5 Chip can bind Anti-CDCP1 CTF Antibody2 with an affinity constant of 153.23 nM as determined in SPR assay (Biacore T200).

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

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

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

The purity of 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 CDCP1.

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

Product List

References

1.    BCG046, a CDCP1 ADC that targets CTF, has demonstrated potent in vitro and in vivo efficacy 

2.    Donahue, Katelyn L, and Marina Pasca di Magliano. “Cleaved CDCP1 marks the spot: a neoepitope for RAS-driven cancers.” The Journal of clinical investigation vol. 132,4 (2022): e157168. doi:10.1172/JCI157168 

3.    Khan, Tashbib 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 vol. 12,16 6915-6930. 3 Oct. 2022, doi:10.7150/thno.78171 

4.    Khan, Tashbib et al. “The CDCP1 Signaling Hub: A Target for Cancer Detection and Therapeutic Intervention.” Cancer research vol. 81,9 (2021): 2259-2269. doi:10.1158/0008-5472.CAN-20-2978 

5.    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 

6.    Lim, Shion A et al. “Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers.” The Journal of clinical investigation vol. 132,4 (2022): e154604. doi:10.1172/JCI154604 

7.    IDP-001 is a potent bispecific ADC with in vivo activity against mouse xenograft tumors models expressing EGFR and CDCP1 

8.    Abstract 4256: HY0001a: A novel antibody-drug conjugate (ADC) targeting CUB domain containing protein 1 (CDCP1) | Cancer Research | American Association for Cancer Research