Pancreatic cancer ADC: Potential Targets and Clinical Advances

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Pancreatic cancer ADC: Potential Targets and Clinical Advances

Pancreatic cancer ADC: Potential Targets and Clinical Advances

Pancreatic cancer is an extremely aggressive form of cancer with a rising incidence, and a 5-year relative survival rate of only about 12%. Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive subtype, accounting for approximately 90% of pancreatic cancer cases.

Surgery remains the sole curative option for some PDAC patients. However, reliable biomarkers or early diagnostic methods are currently lacking, leading to most patients being diagnosed with metastatic disease, making curative surgery difficult.

Thus, chemotherapy remains the best option for metastatic, unresectable PDAC, with a median survival time of only 10-12 months.

Given the limited efficacy of current combination chemotherapy, research in pancreatic cancer treatment has shifted towards targeted therapies and antibody-based approaches.

Antibody Drug Conjugates (ADCs) represent a unique treatment platform that combines the tumor-targeting ability of monoclonal antibodies with the efficacy of cytotoxic drugs.

ADCs consist of three components: a monoclonal antibody targeting a tumor-specific antigen, a cytotoxic drug, and a linker molecule (Figure 1).

ADCs facilitate the tumor-specific delivery of drugs, reducing chemotherapy-related side effects.

Currently, 14 ADCs have received FDA approval for treating hematologic malignancies and solid tumors, including breast cancer, urothelial carcinoma, and HER2+ gastric cancer.

Although there are no ADCs specifically approved for pancreatic cancer, their potential application in this context is gaining increasing attention.

This article summarizes the potential targets and related research of ADCs for pancreatic cancer, as well as the challenges faced and strategies to overcome them.

Pancreatic cancer ADC: Potential Targets and Clinical Advances

Figure 1: Structure of ADC and ADC molecule targeting pancreatic cancer

1. Potential Targets for Pancreatic Cancer ADCs

Selecting appropriate tumor-specific antigens is a crucial factor in developing effective ADCs. Numerous antigens targeting pancreatic cancer and a range of cytotoxic drugs and linker molecules for ADC design have been reported (Figure 1).

Potential ADC targets for pancreatic cancer include Epidermal Growth Factor Receptor (EGFR), Mesothelin, Carcinoembryonic Antigen (CEA or CD66e), also known as CEACAM5, Trop2, Tissue Factor (TF or CD142), Human Epidermal Growth Factor 3 (HER3), CD70 (belonging to the tumor necrosis factor superfamily), Mucin 1 (MUC1), Intercellular Adhesion Molecule 1 (ICAM1 or CD54), Transferrin Receptor 1 (CD71), Glypican-1 (GPC1), Solute Carrier Family 44 Member 4 (SLC44A4), Death Receptor 5 (DR5), etc.

Several preclinical studies have preliminarily confirmed the feasibility of ADC therapy for pancreatic cancer. For example, using two cleavable linker molecules (MC linker or PY linker) to conjugate a humanized anti-EGFR mAb (RC68) to Monomethyl auristatin E (MMAE).

Both linkers showed similar affinity and anti-tumor activity in pancreatic cancer xenograft models, with the PY linker ADC demonstrating superior efficacy over gemcitabine.

2. Clinical Studies of Pancreatic Cancer ADCs

Data from the clinical trial website (www.clinicaltrials.gov) reveals that since 2010, over ten pancreatic cancer ADCs have been in various stages of clinical research (Table 1), with only a few results published.

Table 1: Pancreatic Cancer ADCs in Clinical Trials

Pancreatic cancer ADC: Potential Targets and Clinical Advances

Bayer’s Anetumab ravtansine (AR): Developed by coupling a fully humanized anti-Mesothelin IgG1 mAb with the maytansinoid derivative DM4. An initial phase I study for solid tumors expressing Mesothelin (NCT01439152) showed stabilization in 3 out of 9 pancreatic cancer patients after treatment. An ongoing phase I study (NCT03816358) is evaluating the efficacy of AR in combination with immune checkpoint inhibition and gemcitabine for advanced pancreatic cancer, with 8 patients showing stable conditions as of January 2022.
XB002: Involves a humanized antibody targeting TF, coupled with the novel cytotoxic drug ZymeLink Auristatin, currently in phase I trials (NCT04925284). As of October 2022, 19 patients demonstrated disease stabilization, with 3 continuing treatment (including one pancreatic cancer patient), and clinical trials for single-agent XB002 and combination therapy with nivolumab are planned.
TAK-264 (MLN0264): Formed by coupling a fully humanized guanosine cyclicase C (GCC) IgG1 mAb with MMAE. After promising results in a phase I trial for late-stage gastrointestinal malignancies expressing GCC (NCT01577758), a phase II study (NCT02202785) was conducted on 43 pancreatic cancer patients, with a 3% objective response rate and a median treatment duration of 2 months (range 1-10). The second stage of the study has not been initiated based on mid-term efficacy data.

Other ADC drugs in clinical trials for pancreatic cancer either did not demonstrate superiority or have not yet disclosed relevant data.

Examples include enmetuzumab (NCT02999672, terminated without disclosing pancreatic cancer efficacy data), ASG-5ME (NCT01166490, good tolerance but no difference in objective response rate compared to standard chemotherapy), and AbGn-107 (NCT02908451, data for pancreatic cancer treatment is yet to be disclosed).

Despite the significant success of ADCs in treating hematologic malignancies and breast cancer, they have not shown the same potential in pancreatic cancer clinical trials.

This could be attributed to the aggressive and complex nature of pancreatic cancer, presenting various challenges for ADC drug development.

3. Challenges and Strategies for Pancreatic Cancer ADCs

Precise targeting of tumor antigens is crucial for the success of ADCs, and determining the optimal target for pancreatic cancer treatment remains inconclusive.

Some studies suggest that targeting the tumor stroma is a promising approach, such as Glypican-1 on tumor-associated fibroblasts (CAFs) or Tumor Endothelial Marker 8 (TEM8).

These strategies may aid in the delivery and penetration of ADCs into tumor tissues, delivering cytotoxic drugs to the tumor microenvironment in a tumor-specific, target-independent manner.

The pancreatic cancer microenvironment is characterized by strong connective tissue proliferation, lack of vascular distribution, and potent immunosuppression, which may limit the efficacy of ADCs. The strategy to improve this involves reducing the molecular size of ADCs to enhance their pharmacological properties.

Researchers have developed a nanobody ADC targeting the cancer antigen 5T4, coupled with SN-38 (a topoisomerase inhibitor). This nanobody ADC demonstrated good tumor accumulation and penetration in pancreatic cancer organoids and xenograft models.

Pancreatic cancer ADC: Potential Targets and Clinical Advances

Figure 2: Strategies to enhance the efficacy of pancreatic cancer ADCs

Combination therapy is an effective strategy in cancer treatment. Gemcitabine resistance is common in pancreatic cancer, often necessitating combination therapy with other chemotherapy drugs such as albumin-bound paclitaxel.

TR1801-ADC, targeting MET with the PBD toxin Tesirine, showed synergistic effects with gemcitabine in a human pancreatic cancer xenograft model, improving gemcitabine resistance.

Clinical studies combining gemcitabine and TR1801-ADC, such as the trial evaluating the efficacy of Tusamitamab ravtansine as monotherapy and in combination with gemcitabine in metastatic pancreatic cancer (NCT04659603), are underway.

Clinical trial data for the combination therapy of AR with gemcitabine and nivolumab showed stability in all 8 treated patients (NCT03816358).

Due to the strong immunosuppressive tumor microenvironment in pancreatic cancer, immunotherapy options are limited.

Designing ADCs that combine cytotoxic and immunomodulatory properties to induce DNA damage and increase dendritic cell maturation and MHC antigen presentation may help overcome the low immunogenicity of pancreatic cancer.

The immunomodulatory properties of cytotoxic drugs and their synergy with immunotherapy have become a focus of ADC research.

MGC018, an ADC targeting PD-1 with Duocarmycin, demonstrated effectiveness in pancreatic cancer models and human PD-1-expressing mouse models, indicating synergy with immune checkpoint inhibitors.

MGC018 is currently undergoing phase I clinical trials (NCT05293496), combined with the dual-specificity DART molecule targeting CTLA-4 and PD-1 (Lorigerlimab) for pancreatic cancer and other solid tumors.

While surgery remains the only cure for pancreatic cancer patients, less than 20% are eligible for surgery at the time of diagnosis.

Clinical guidelines recommend neoadjuvant therapy for resectable and locally advanced pancreatic cancer, aiming to control early systemic spread and increase tumor-free margins, thereby extending the survival of late-stage patients and improving resection rates.

Neoadjuvant ADC therapy has been explored in other cancers, such as the ongoing clinical study of Trastuzumab deruxtecan as neoadjuvant therapy for HER2-low-expressing breast cancer (NCT04553770), and Brentuximab vedotin has become a neoadjuvant drug for lymphoma treatment.

Considering the potential applications of ADCs in other cancers, ADCs as neoadjuvant therapy for pancreatic cancer are also considered to have some potential.

Conclusion

ADCs show broad prospects in the treatment of pancreatic cancer.

While numerous clinical trials for pancreatic cancer ADCs have been conducted, the clinical translation of this therapy has not yet been realized.

The major challenges facing pancreatic cancer ADCs may include the complex tumor microenvironment and low tumor penetration efficiency of ADCs.

Despite these challenges, the ADC technology platform allows for multifunctionality and diversity, offering limitless possibilities for customizing pancreatic cancer ADCs.

Future research should focus on enhancing effectiveness by customizing ADCs targeting the pancreatic cancer microenvironment.

Additionally, the significant potential of combining ADCs with other drugs to enhance anti-tumor immune responses and improve efficacy against pancreatic cancer should not be overlooked.

Although ADCs have not yet been applied in pancreatic cancer treatment, ongoing research suggests that pancreatic cancer ADCs could still provide clinical benefits with further exploration.

Pancreatic cancer ADC: Potential Targets and Clinical Advances

Original Article Citation: N Wittwer, M Brown, V Liapis, A Staudacher. Antibody drug conjugates: hitting the mark in pancreatic cancer? Journal of Experimental & Clinical Cancer Research. 2023,42(1):280. (DOI: 10.1186/s13046-023-02868-x)

(source:internet, reference only)

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