1. Introduction

In the absence of reliable biomarkers for use in the screening and early detection of pancreatic cancer, and more effective and less toxic therapeutic agents, it has been projected that pancreatic cancer will not only rise in incidence but also will take over breast, prostate and colorectal cancers and become the second leading cause of cancer death in the Western world by 2030 ^[1][2][3].

Treatment of patients with pancreatic cancer involves surgery, chemotherapy and radiotherapy. Although surgery is the only curative treatment, around 80% of patients are diagnosed at late stages of the disease and are not eligible for surgical resection. Adjuvant treatment with chemotherapy is beneficial given the high rate of locoregional relapse after surgery alone. Gemcitabine-based therapy was traditionally the mainstay for treatment of pancreatic cancer ^[4]. However, the results of the recently published ESPAC-4 trial showed that the combination of gemcitabine plus capecitabine increased median overall survival compared to gemcitabine alone (28.0 vs 25.5 months) with an acceptable toxicity profile, and an estimated 5-year survival of 28.8% for the combination group compared to 16.3% with gemcitabine monotherapy, making this combination the new standard of care in the adjuvant setting ^[5]. Treatment for borderline resectable or locally advanced unresectable tumours seems to yield better results with chemotherapy (e.g., FOLFIRINOX) rather than chemoradiotherapy, although more robust evidence from trials is needed ^[6].

Patients with metastatic disease are treated with either FOLFIRINOX or gemcitabine plus nab-paclitaxel as first-line in patients with good performance status ^[7][8]. Erlotinib was approved by the FDA for use in metastatic pancreatic cancer patients based on a study that showed a modest improvement in median survival in patients who received erlotinib plus gemcitabine compared to gemcitabine alone (6.4 vs 5.9 months) but the clinical relevance is controversial ^[9]. The combination of liposomal irinotecan, fluorouracil and folinic acid (NAPOLI-1 regimen) is the only currently approved second-line chemotherapy for patients with metastatic pancreatic cancer based on a phase 3 trial that showed median overall survival of 6.1 months for the triple combination compared to 4.2 months in patients receiving fluorouracil and folinic acid ^[10]. Therefore, it is essential to discover novel targets and to develop more effective, less toxic and pancreatic cancer specific therapeutic agents for the long-term benefit of patients with pancreatic cancer.

The advent of hybridoma technology by Köhler and Milstein in 1975, which allows the production of unlimited quantity of an antibody against any target antigen, has revolutionised many areas of biomedical research and medicine ^[11]. Further technological advances in genetic engineering allowed the production of less immunogenic and more effective types of mAbs (e.g., chimeric, humanised, fully human mAbs, antibody fragments and bispecific antibodies) for use in the treatment of patients with a range of diseases including cancer ^{[12][13][14][15][16]}. Indeed, mAb-based therapy is currently one of the two major types of targeted therapy and an attractive therapeutic alternative for the treatment of patients with a wide range of cancers. In this article, we provide a comprehensive review of monoclonal antibody-based agents that have been approved for the treatment of human cancers and the current state of preclinical and clinical studies with monoclonal antibody-based agents in pancreatic cancer. We shall also highlight some of the contributing factors for the poor response to therapy with mAbs, and emerging opportunities for more effective treatment of pancreatic cancer with antibody-based agents in combination with other treatments.

2. Therapeutic Antibodies Approved in Cancer

Over the past few decades, monoclonal antibody-based agents have been approved and used routinely in the treatment of a wide range of human diseases including cancer, infectious, autoimmune and metabolic diseases. Monoclonal antibody-based drugs can be developed by a variety of approaches such as hybridoma technology, phage display technology, the use of transgenic mouse or the single B-cell technique ^[15][17][18].

Depending on the target antigen and the antibody format, monoclonal antibody-based drugs can produce their anti-tumour activity by several mechanisms (Figure 1). Some mAbs are directed against growth factor receptors with high levels of expression in tumours cells and inhibit tumour growth by blocking the binding of growth factor to its receptor (e.g., anti-EGFR mAbs cetuximab and panitumumab), or by inhibiting receptor dimerization (e.g., anti-HER-2 mAb pertuzumab), consequently inhibiting the downstream cell signalling pathways. In contrast, other antibodies halt tumour growth by inhibiting angiogenesis (e.g., anti-VEGF blocking mAb bevacizumab), stimulating apoptosis (e.g., anti-CD20 mAb rituximab) or delivering lethal doses of radioisotopes (e.g., ibritumomab tiuxetan), or toxins to tumour sites (e.g., brentuximab vedotin, an anti-CD30 mAb conjugated to anti-microtubule agent monomethyl auristatin E). Other mAbs induce tumour killing by immune-mediated antibody-dependent cellular cytotoxicity (ADCC)/complement-dependent cytotoxicity (CDC, e.g., rituximab, trastuzumab) and immune checkpoint inhibition through targeting of PD-1/PD-L1 and CTLA-4 (e.g., nivolumab, pembrolizumab, atezolizumab, ipilimumab). Finally, other therapeutic mAbs are used as component of CAR-T cells, or as bispecific antibodies that induce tumour killing by simultaneous targeting of two different antigens on tumour cells, or bispecific immune cell engager by targeting one antigen on tumour cells and another antigen on T cells (e.g., catumaxomab, blinatumomab, Figure 1).

Figure 1. Mechanisms of action of monoclonal antibody-based products. (A) Targeting growth factor receptors, blocking the binding of an activating ligand and inhibiting receptor homo- and heterodimerization; (B) Targeting of tumour vasculature receptor or its ligands inhibiting angiogenesis; (C) Induction of apoptosis by recruitment of immune effector cells (ADCC) or activation of the complement cascade (CDC), and the use of antibody-based molecules to engineer T lymphocytes (CAR T cells); (D) Immune checkpoint inhibition by blockade of the PD-1/PD-L1 axis or CTLA-4 inhibitory receptors, increasing cytotoxic T cell activity; (E) Simultaneous targeting of two antigens, one on tumour cells and one on effector T cells, by using bispecific antibodies (BITE, bispecific T-cell enhancing); and (F) Delivery of payloads such as toxins and radioisotopes to tumour cells. Created with BioRender.com (accessed on 17 March 2021).

To date, 45 mAbs have been approved in the USA and/or the European Union (EU) for the treatment of patients with a wide range of cancers (Table 1). In particular, there has been a great deal of research interest in this area in recent years and a growing number of mAb approvals for different indications. Indeed, with the exception of checkpoint inhibitors, nearly half of the approved therapeutic antibodies are directed against one of the following six target antigens: CD19, CD20, the two members of the human epidermal growth factor receptor (HER) family namely EGFR and HER-2, VEGF and VEGFR (Table 1). Interestingly, several immune checkpoint inhibitors such as anti-CTLA-4 mAb ipilumumab, anti-PD-1 mAbs pembrolizumab and nivolumab, and anti-PD-L1 mAbs avelumab and durvalumab have been approved for a wide range of cancer types. Moreover, additional mAbs have been approved outside the USA and EU for treatment of various cancer types including nimotuzumab (in head and neck cancer, nasopharyngeal cancer and glioma) and vivatuxin (in lung cancer) ^[14].

Table 1. Monoclonal antibodies approved in the U.S. and/or European Union for cancer treatment.

ADC: antibody drug conjugate; ALCL: anaplastic large cell lymphoma; ALL: acute lymphoblastic leukaemia; AML: acute myeloid leukaemia; auto-HSCT: autologous hematopoietic stem cell transplantation; BCG: Bacillus Calmette-Guerin; B-CLL: B-cell chronic lymphocytic leukaemia; BCMA: B-cell maturation antigen; cHL: classical Hodgkin lymphoma; CLL: chronic lymphocytic leukaemia; CRC: colorectal cancer; CSCC: cutaneous squamous cell carcinoma; CTLA-4: cytotoxic T lymphocyte antigen-4; DLBCL: diffuse large B-cell lymphoma; dMMR: mismatch repair deficient; EGFR: epidermal growth factor receptor; EpCAM: epithelial cell adhesion molecule; FL: follicular lymphoma; GBM: glioblastoma multiforme; GD2: surface disialoganglioside GD2; GEJ: gastroesophageal junction; GM-CSF: granulocyte-macrophage colony-stimulating factor; HCC: hepatocellular carcinoma; HER-2: human epidermal growth factor receptor-2; HNSCC: head and neck squamous cell carcinoma; MM: multiple myeloma; MMAE: monomethyl auristatin E; MRD: minimal residual disease; MSI-H: microsatellite instability-high; NHL: non-Hodgkin lymphoma; NSCLC: non-small-cell lung cancer; pcALCL: primary cutaneous anaplastic large cell lymphoma; PDGFRα: platelet-derived growth factor receptor alpha; PD-1: programmed death-1 receptor; PD-L1: programmed death ligand-1; PMBCL: primary mediastinal large B-cell lymphoma; RANKL: receptor activator of nuclear factor-kappa B ligand; RCC: renal cell carcinoma; R/R: relapsed or refractory; SCLC: small cell lung cancer; SCT: stem cell transplant; SLAMF7: signalling lymphocytic activation molecule F7; TNBC: triple-negative breast cancer. VEGF: vascular endothelial growth factor; VEGFR-2: vascular endothelial growth factor receptor 2. * withdrawn; Taken from: https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. Updated as of 12 March 2021.

However, despite such advances, to date no antibody-based drugs have been approved for the treatment of patients with pancreatic cancer ^[19]. Some of the contributing factors are the harsh desmoplastic microenvironment of pancreatic cancer, the heterogeneous nature of tumours and the lack of reliable predictive biomarkers and companion diagnostic tests to select patients who are more likely to respond to such therapy ^{[20][21][22][23]}. In the following sections, we discuss the results of preclinical studies and clinical trials with antibody-based agents in pancreatic cancer. We will also highlight the importance of antibody-based technology and other approaches in the discovery of cell surface antigens with high levels of expression in pancreatic cancer (i.e., additional therapeutic targets) and in the development of mAb-based targeted therapy for patients with pancreatic cancer.