Pancreatic Cancer ADC: Opportunity or Challenge?

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Pancreatic Cancer ADC: Opportunity or Challenge?

Pancreatic Cancer ADC: Opportunity or Challenge?

Pancreatic cancer, with its rising incidence and a mere 12% 5-year relative survival rate, remains an aggressively invasive disease. Pancreatic ductal adenocarcinoma (PDAC), constituting 90% of pancreatic cancers, is both the most common and aggressive form.

Surgery stands as the primary cure for some PDAC patients, yet the lack of reliable biomarkers or early diagnostic methods often leads to late-stage diagnoses, hindering curative surgical interventions.

Chemotherapy remains the optimal treatment for metastatic and unresectable PDAC, but the median survival time for pancreatic cancer patients is only 10-12 months. Given the limited efficacy of current combination chemotherapy, research focus in pancreatic cancer treatment has shifted toward targeted therapies and antibody-based approaches.

Antibody-Drug Conjugates (ADCs) represent a unique therapeutic platform, combining the tumor-targeting capabilities of monoclonal antibodies with the efficacy of cytotoxic drugs. ADCs consist of three components: a monoclonal antibody targeting tumor-associated antigens, a cytotoxic drug, and a linking molecule. ADCs facilitate the tumor-specific delivery of drugs, reducing chemotherapy-related toxicities. Customization allows ADCs to meet a range of pharmacological and clinical needs.

While 14 ADCs have gained FDA approval for treating hematologic and solid tumors, including breast cancer, urothelial carcinoma, and HER2+ gastric cancer, there are currently no ADCs specifically approved for pancreatic cancer. Nevertheless, the potential application of ADCs in pancreatic cancer has garnered increasing attention.

This article summarizes the targets and related research of ADCs for pancreatic cancer, the challenges they face, and strategies to overcome these challenges.

Pancreatic Cancer ADC: Opportunity or Challenge?

Potential Targets for Pancreatic Cancer ADCs:

Data from the clinical trial website (www.clinicaltrials.gov) show that since 2010, more than ten pancreatic cancer ADCs are in clinical research at different stages (Table 1) , and only a few results have been published so far.

Table 1 Pancreatic cancer ADCs in clinical trials

Pancreatic Cancer ADC: Opportunity or Challenge?

Anetumab ravtansine (AR) developed by Bayer is formed by conjugating fully human mesothelin IgG1 mAb with maytansine derivative DM4. AR was initially conducted in a phase I study in mesothelin-expressing solid tumors (NCT01439152) . Three of the nine patients with pancreatic cancer included in the study were in stable condition after treatment. A phase I study is currently underway to evaluate the efficacy of AR combined with immune checkpoint inhibition and gemcitabine in the treatment of advanced pancreatic cancer (NCT03816358) . As of January 2022, 33 patients have been included, of which 8 patients who received AR combined with nivolumab and gemcitabine are all in stable condition. The trial of AR combined with nivolumab and gemcitabine will continue in an expanded cohort based on disease control rate and tolerability data, which is currently ongoing.

XB002 contains a humanized antibody targeting TF conjugated to the novel cytotoxic drug ZymeLink Auristatin and is currently in Phase I trials (NCT04925284). As of October 2022, the condition of 19 patients is stable, of which 3 are still receiving treatment (1 is a patient with pancreatic cancer) , and clinical trials of XB002 monotherapy and combination therapy with nivolumab are planned.

TAK-264 (MLN0264) is formed from a fully human guanylyl cyclase C (GCC) IgG1 mAb conjugated to MMAE. The first human trial of TAK-264 was conducted in patients with advanced gastrointestinal malignancies expressing GCC (NCT01577758) . Two patients with pancreatic cancer included in the study were in stable condition and had long-lasting curative effect after treatment. Therefore, a further phase II study of TAK-264 (NCT02202785) was conducted. The study included 43 patients with pancreatic cancer, with an objective response rate of 3% and a median treatment cycle of 2 (range 1-10) . 36 patients discontinued the trial due to disease progression. Based on interim efficacy data, the second phase of the study has not yet begun.

There are also some clinical trials of ADC drugs that have not shown advantages in the treatment of pancreatic cancer or the relevant data have not yet been published, such as: trastuzumab (NCT02999672, the trial was terminated early and the efficacy data of pancreatic cancer was not published), ASG-5ME (NCT01166490, well tolerated but no difference in objective response rate compared with conventional chemotherapy), AbGn-107 (NCT02908451, relevant data for the treatment of pancreatic cancer have not yet been published). Although ADCs have had great success in treating hematological tumors and breast cancer, they have not shown the same potential in clinical trials for pancreatic cancer. This may be due to the aggressiveness and complexity of pancreatic cancer, which poses many challenges to the development of ADC drugs.

Clinical Trials of Pancreatic Cancer ADCs:

Selection of appropriate tumor-specific antigens is a key factor in obtaining effective ADCs. A number of antigens targeting pancreatic cancer have been reported as well as a range of cytotoxic drugs and linker molecules for designing ADCs (Fig. 1) .

ADC targets with development prospects include : epidermal growth factor receptor (EGFR) , mesothelin , carcinoembryonic antigen (CEA, or CD66e) , also known as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) , trophoblast cell surface antigen 2 (Trop2) , tissue factor (TF or CD142) , human epidermal growth factor 3 (HER3) , CD70 (a member of the tumor necrosis factor superfamily) , mucin 1 (MUC1) , intracellular adhesion Molecule 1 (ICAM1 or CD54) , transferrin receptor 1 (CD71) , glypican 1 (GPC1) , choline transporter-like protein 4 (SLC44A4) , death receptor 5 (DR5) , etc.

Several preclinical studies have preliminarily confirmed the feasibility of ADC in treating pancreatic cancer, such as using two cleavable linker molecules (MC linker or PY linker) to couple humanized anti-EGFR mAb (RC68) to Monomethyl auristatin E (MMAE) .

PY linker’s ADC showed higher serum stability, and both ADCs showed similar affinity and anti-tumor activity in pancreatic cancer xenograft models, with better efficacy than gemcitabine.

Challenges and Strategies for Pancreatic Cancer ADCs:

Precise targeting of tumor antigens is crucial for ADC success, and identifying the optimal target for pancreatic cancer treatment remains uncertain. Strategies targeting the tumor stroma, such as Glypican-1 on Cancer-Associated Fibroblasts (CAFs), show promise in enhancing ADC delivery and tumor penetration.

The pancreatic cancer microenvironment, characterized by dense fibrosis, poor vascularization, and strong immunosuppression, may limit ADC efficacy. Modification strategies, such as reducing ADC size, aim to improve pharmacological properties.

Pancreatic Cancer ADC: Opportunity or Challenge?

Combination therapy, particularly with gemcitabine, is explored to enhance ADC efficacy. Immunomodulatory features of cytotoxic drugs within ADCs present a research focus, with potential synergies with immunotherapies.

ADCs as neoadjuvant therapy for pancreatic cancer, though unexplored, hold promise based on their success in other cancers.

Conclusion:

ADCs hold substantial promise for pancreatic cancer treatment, with numerous ongoing clinical trials.

Challenges such as the complex tumor microenvironment and low intra-tumoral penetration efficiency need to be addressed. Despite these hurdles, the ADC technology platform provides limitless possibilities for customizing pancreatic cancer ADCs.

Future research should focus on tailoring ADCs to target the pancreatic cancer microenvironment effectively.

Additionally, combining ADCs with other drugs to enhance anti-tumor immune responses holds significant potential.

While ADCs have not yet been applied in pancreatic cancer treatment, ongoing research suggests that pancreatic cancer ADCs may still provide clinical benefits in the future.