Historical Perspective: What Makes Antibody-Drug Conjugates Revolutionary?

Lynn J. Howie and Kimberly L. Blackwell

Division of Medical Oncology, Duke Cancer Institute, Durham, NC, USA

Introduction

Developing drugs that are able to target disease and spare healthy tissue has been a long-time goal of both oncologic and non-oncologic drug development. Since the late nineteenth century, it has been recognized that effective treatment of disease by therapeutic agents is improved when therapeutics demonstrate selectiveness for foreign bodies (bacteria) or diseased cells and spare healthy cells. The development of novel and highly selective antibody-drug conjugates (ADCs) has moved us closer to this goal in cancer therapy (Figure 1). Agents such as trastuzumab emtansine (T-DM1) and brentuximab vedotin have shown promising results, particularly in patients with advanced disease who have progressed on other treatments. Combining cancer-specific antibody targets with potent cytotoxic therapies makes these agents revolutionary in their efforts to deliver potent treatments while minimizing adverse effects, coming closer to the "magic bullet" concept of Ehrlich and other early twentieth-century pharmacologists [1].

Figure 1 Timeline of events in development of ADCs.

Early Work in Monoclonal Antibody Development: Ehrlich's Magic Bullets

Ehrlich and colleagues hypothesized that there may be antigens specific to tumors and bacteria that could be targeted with drugs for the treatment of cancer and infectious disease. Throughout the 1960s and 1970s, there was much work to develop specific antibodies that could be easily generated in large quantity and used for therapeutics. In a 1975 letter to the journal Nature, Georges Kohler and César Milstein described the development of a mechanism to generate large quantities of antibodies with a defined specificity by fusing myeloma cells that reproduce easily in cell culture with mouse spleen cells that are antibody-producing cells [2]. By combining these two types of cells, a continuous supply of specific antibody was produced in quantities sufficient for use as therapeutic agents. As with the production of other human proteins, the use of microbial agents for antibody production further advanced the field, as these methods were able to generate antibody and antibody fragments in the quantities needed for drug development [3-5].

Subsequent work demonstrated that monoclonal antibodies could be used to identify and characterize the multiple different types of surface receptors found on cells [6, 7]. These receptors could then be used as targets for cancer therapeutics with better tumor specificity and potentially less toxicity.

Use of Monoclonal Antibodies to Identify and Treat Cancer

Early on, the potential for monoclonal antibodies in the detection and treatment of cancer was recognized as promising [8, 9]. The use of antibodies to improve tumor localization was of great interest in the 1970s and 1980s and was a first step in transitioning the use of these antibodies from tumor identification to tumor treatment [10]. Radioactive iodine was conjugated to a tumor-associated monoclonal antibody to effectively deliver cytotoxic doses of radiation to tumor sites in women with metastatic ovarian cancer with lower doses of radiation to surrounding tissues and the remainder of the body [11].

During the 1980s and 1990s, the development of monoclonal antibodies for therapeutic treatment of cancers delivered promising results. In 1997, rituximab, an anti-CD20 monoclonal antibody that targets malignant B cells, was initially approved for use in relapsed follicular lymphoma [12]. Trials demonstrated that in low-grade lymphomas, this agent had a response rate of 48%. Importantly, this therapy was relatively well tolerated with only 12% grade 3 and 3% grade 4 toxicity [13]. Subsequent trials established the role of rituximab in aggressive B-cell lymphomas as it significantly improved survival when added to standard chemotherapy [14-16].

Following the initial approval of rituximab, trastuzumab was approved in 1998 for the treatment of human epidermal growth factor receptor-2 (HER2) overexpressing metastatic breast cancer (MBC). Based on significant survival benefits in phase III clinical trials, this agent was approved in combination with paclitaxel for the first-line treatment of HER2 overexpressing MBC and as a single agent for those who had progressed on one or more previous chemotherapy regimens [17]. Similar to rituximab, trastuzumab was well tolerated with few side effects. The main safety signal reported was cardiomyopathy that was primarily seen when used in combination with anthracycline-containing regimens [18, 19]. Subsequently, a number of other agents were approved for use in solid tumor malignancies including those that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Table 1 is a comprehensive listing of monoclonal antibody that have been approved along with their approval dates and indications.

Table 1 Monoclonal antibodies directed at malignant cell surface receptors.

Abbreviations: CLL, chronic lymphocytic leukemia; GE, gastroesophageal.

Although these agents have provided therapeutic benefits, there have been multiple efforts to enhance the efficacy of monoclonal antibodies. This has been done in a variety of ways including the development of monoclonal antibodies that target immune cells [24, 25], the development of bispecific monoclonal antibodies that target multiple cell surface receptors and link malignant cells with host immune cells [26], and the development of monoclonal antibodies through the conjugation of radioisotopes for the targeted delivery of cytotoxic radiation [27, 28]. Examples of these agents are found in Table 2.

Table 2 Additional monoclonal antibodies approved for use.

Linking Monoclonal Antibodies with Cytotoxic Agents

The linkage of monoclonal antibodies to potent cytotoxic drugs is a further step toward enhancing the efficacy of these agents in cancer treatment. Although specific cell surface receptors on malignant cells may not be directly involved in tumor proliferation, receptors that are identified as unique to tumor cells can allow for targeted delivery of cytotoxic agents. An effective ADC consists of three primary components: a monoclonal antibody that recognizes a cell surface receptor that is expressed primarily on malignant cells, a linking agent, and a potent cytotoxic agent that is known as the "payload" [29].

Much work has been devoted to improving the linking molecule between the monoclonal antibody and the cytotoxic agent as this is a crucial component of drug stability and potency. Effective linkers are able to maintain the cytotoxic agent on the monoclonal antibody such that it is trafficked to the targeted cancer cell and then transported into the cell where the link is then cleaved within the lysosome. This linkage allows potent cytotoxic whose dosing is limited by its toxicity to be delivered directly to malignant cells and improves the therapeutic index of these agents. Improvements in the identification...