For decades, investigators have been looking for ways to combine the optimal aspects of different types of anticancer therapy to create more effective, safer drugs. As researchers gain a better understanding of the unique aspects of individual tumor types and their surrounding microenvironment, the design of novel therapies categorized as prodrugs is become increasingly sophisticated, and several novel constructs show particular promise.
The term prodrugs refers to a broad group of therapies designed to remain inactive until they reach their intended target. It also encompasses a wide variety of mechanisms for the delivery and activation of anticancer therapies.
Thus far, antibody–drug conjugates (ADCs) have been the most promising class of prodrugs in anticancer therapy, with several agents now approved by the FDA. Beyond that, other prodrugs with diverse mechanisms of action have gained oncology indications.1
A recent article in Nature Reviews Drug Discovery
identified at least 30 prodrugs that the agency has approved in the past decade across all clinical categories, including 5 for cancer, that in total account for more than 12% of the small molecule new chemical entities authorized during that time.1
Despite disappointments in the field, some observers expect prodrug strategies to be an important facet of future drug development for cancer and other disease states.1,2
Prodrug: A Broad Label
The term prodrug
was coined in the 1950s3
and has been explored as a drug design strategy ever since. It refers to an inactive or less active derivative of a drug molecule that can be transformed into the active form via some sort of chemical or enzymatic activity.
Prodrugs are designed to modify the physical and chemical characteristics of a drug to make it more effective. A prodrug strategy can help ensure that a drug is active just at a particular time or place to both maximize cancer cell killing and minimize off-target toxicity. It can improve the bioavailability, solubility in water, metabolism, absorption, or route of administration of a drug, as well as its ability to overcome physiological barriers, such as the blood–brain barrier and the gastrointestinal tract epithelium.
The plethora of prodrug strategies that have been tested can be separated into 2 major categories, based on the way in which they are converted into the active form. Passively activated prodrugs exploit the differences between cancerous and normal cells, such as the overexpression of certain cell surface receptors by cancer cells, or the unique nature of the microenvironment surrounding the tumor, such as lower pH, reduced oxygen levels, and aberrant vasculature. Prodrugs can also be “turned on” via active strategies, such as by simultaneously introducing a secondary activating drug or substance to the patient.4-6
Figure. Antibody-Drug Conjugates in Action8
ADCs represent the most promising form of prodrug therapy to date. They are composed of a monoclonal antibody that targets a specific tumor-associated antigen linked to a chemotherapeutic agent, which, in theory, enables targeted delivery of the cytotoxic “payload” to the tumor (Figure
The design of the linker between antibody and drug is a vitally important consideration. It must be broken at precisely the right time to ensure maximum efficacy and prevent release of the cytotoxic drug into the circulation. Numerous designs, including acid-sensitive linkers, protease-sensitive linkers, and glutathione-sensitive linkers, are intended to exploit the low pH of the tumor microenvironment, the specific enzymes expressed by tumor cells, and the high levels of glutathione, respectively.6-8
The FDA has approved 4 ADCs for these targets and tumor types: ado-trastuzumab emtansine (Kadcyla) for HER2 in metastatic breast cancer; brentuximab vedotin (Adcetris), CD30 in Hodgkin and anaplastic large cell lymphoma; inotuzumab ozogamicin (Besponsa), CD22 in acute lymphoblastic leukemia (ALL); and gemtuzumab ozogamicin (Mylotarg), CD33 in acute myeloid leukemia (AML). A variety of ADCs are among the prodrugs in clinical development, many of which are in phase III trials (Table
), suggesting the list of FDA-approved agents may expand in the near future.9-10
Less Conventional Chemotherapy
ADCs are an example of a carrier-linked prodrug, wherein the parent drug itself is not modified but attached to a secondary molecule that dictates its activity. Alternatively, prodrugs can involve specific alterations to the parent drug.
Various types of chemotherapy-based prodrugs fall into this second category. Cyclophosphamide is a prodrug of phosphoramide mustard, a DNA cross-linking agent, that is activated only in cells that have low levels of aldehyde dehydrogenase. Temozolomide, another prodrug, is a derivative of the alkylating agent dacarbazine.