Abstract
Introduction: Antibody drug conjugates (ADCs) are a class of therapeutics that combine the selective targeting properties of monoclonal antibodies (mAbs) with potent cell killing activities of cytotoxic agents. Given rapid pace of progress in this field, it is important for drug developers to have a high level view of the landscape of ADCs in the clinic. This review analyzes ADCs tested in the field of Oncology. Trials are evaluated by cancer type, trial status, phase, and characteristics of the ADC.

Methods: Two databases were used to evaluate current clinical studies: ClinicalTrials.gov and TrialTrove. After cross-referencing the results from each database, a total of 238 unique clinical trials were identified and analyzed.

Results: The clinical testing of ADCs is currently being performed predominantly in hematological malignancies (n=146). Among these, leukemia is the leading indication tested (n=77). There are 89 trials in solid tumors, with breast cancer being the most abundant (n=39). A significant number of clinical trials are in phase II (n=83). There are 47 unique ADCs in clinical trials. Among these ADCs, tubulin inhibitors are the most common warheads used. These are mainly the maytansinoids (n=22) and auristatins (n=16).

MabPlex
ADC Bio
Lonza
 

Conclusion: Our visualization of the clinical landscape of ADCs will help foster the design of future research efforts in this area of great clinical and scientific interest.


1.0 Introduction
The increasing global incidence of cancer and associated resistance patterns necessitates new treatment modalities to serve the patient population [1] [2] [3]. A number of methods are currently employed for cancer treatment including surgery, chemotherapy, hormonal therapy, radiation therapy, adjuvant therapy, cancer targeted therapies, and immunotherapy [4] [5]. The use of biologics in immunotherapy is of particular value to cancer treatment due to the selective nature of monoclonal antibodies (mAbs). These mAbs are able to bind to cells expressing a specific target antigen with high affinity and potentially decrease off-target toxic effects [6] [7]. The biotechnology industry is investing approximately one quarter of its resources in the development of mAbs while also devising next generation platforms to increase both drug efficacy and safety [6].

A number of strategies are currently available to utilize the properties and enhance the functionality of mAbs by coupling diverse moieties to the antibody. These include antibody-radionuclide conjugates, antibody-RNA conjugates, antibody-antibiotic conjugates, antibody-protein conjugates, antibody-fluorophore conjugates, antibody-enzyme conjugates, antibody-cytokine conjugates, and antibody-drug conjugates [5] [7] [8].

Antibody-drug conjugates (ADCs) provide a unique platform whereby naked mAbs are enhanced through conjugation with cytotoxic small molecule drugs. ADCs consist of three main components: the monoclonal antibody (mAb), the cytotoxic molecule (also referred to as the warhead), and the linker. As single agents, mAbs have greater specificity and a more favorable safety profile, but have limited antitumor responses [5] [9]. Small molecule cytotoxins have potent cell-killing activity, but also have significant toxic effects [5]. The linker is the molecular bridge that conjugates the small-molecule cytotoxin to the mAb. The linker and warhead together are termed the payload [Figure 1; Click to enlarge] [10].

Figure 1
Figure 1

When combined, ADCs facilitate the delivery of highly potent cytotoxic molecules directly to tumor cells expressing unique antigens that are specific to the mAb. As a result, ADCs also have the potential to increase the therapeutic window of non-selective cytotoxic agents [5] [7] [9] [10]. Clinical evaluations of ADCs compared to unconjugated mAbs have demonstrated better response rates to the same cellular targets in similar patient populations. These results reinforce the use of ADCs as a promising treatment modality for use in Oncology [5] [11]

The ADC complex is engineered to remain stable after administration until the cellular target is reached [5]. The initial step in the ADC mechanism of action is the binding of the mAb to the target antigen on the cancer cell. Once the ADC is localized to the cell surface, the entire complex consisting of the mAb and payload is internalized through receptor-mediated endocytosis. Upon internalization, the ADC is trafficked to intracellular organelles where the linker is degraded, causing the warhead to be released inside the cell [5] [9] [10] [11]. Subsequently, the warhead disrupts cell division via a cytotoxin-specific mechanism, which ultimately causes cell cycle arrest and apoptosis. Two mechanisms of cell cycle arrest are currently utilized, one mechanism pertains to inhibition of tubulin polymerization as seen in auristatins and maytansines while the other mechanism is based on direct binding to DNA and subsequent inhibition of replication as seen in calicheamicins, duocarmycins, and pyrrolobenzodiazepines (PBDs) [10] [12].

In this review, ADCs used in clinical trials are evaluated in open, completed, closed, or terminated studies. Through evaluation of the global ADC portfolio available in clinical trial databases, it is the intention of this review to create a better understanding of the current clinical landscape.

2.0 Methods

Data Collection 
The current review evaluates data on clinical trials using ADCs as a treatment regimen in the Oncology setting. The databases used to select clinical trials included the clinical database of the National Institutes of Health (www.ClinicalTrials.gov) and TrialTrove®(www.citeline.com/products/trialtrove/). The most updated search of the databases was completed on March 4th, 2014.

ClinicalTrials.gov 
ClinicalTrials.gov [13] is a database maintained by the National Library of medicine (NLM) at the National Institutes of Health (NIH) which contains information on clinical studies provided and updated by the sponsor or principal investigator of the study. The search terms used in this database contained “‘Antibody Drug Conjugate’ OR ‘ADC’ OR ‘Antibody Drug Conjugates’” with “All Studies” selected for recruitment, study results, and study type. The phases selected for the search included “Phase 1, Phase 2, Phase 3, and Phase 4.” A total of 521 trials were generated from ClinicalTrials.gov given the search criteria listed above.

Of the 521 trials, those that were not testing in the oncology therapeutic area (n=281) were eliminated. The studies were further filtered to ensure that ADCs were used in the cohorts as single-arm, in combination, or in comparison with another drug or a number of drugs. Studies which did not test ADCs (n=172) were eliminated, resulting in 68 clinical studies testing ADCs in oncology. All studies taken from this database had NCT numbers as trial identifiers.

TrialTrove 
TrialTrove® [14] is a Citeline product which comprehensively documents pharmaceutical clinical trials in eight therapeutic areas and 180 disease settings. To locate relevant clinical trials on TrialTrove®, the search criteria were restricted to “Oncology” as the therapeutic area and “Antibody Drug Conjugates” or “ADC” as the therapeutic class. Trial phases “I, I/II, II, II/III, III, and IV” were selected as well as “Open, Closed, Temporarily Closed, Completed, and Terminated” for the trial status. A total of 345 trials were generated from the TrialTrove® search given the search criteria listed above.

The 345 studies were further filtered to ensure that ADCs were used in the cohorts as single-arm, in combination or in comparison with another drug or a number of drugs. Studies which included either fusion proteins or immunotoxins (n=23) were removed as these biologics are not considered to be ADCs, resulting in a total of 322 evaluable clinical trials. Additionally, studies that did not have NCT numbers linking them to the NIH database (n=89) were eliminated, resulting in a total of 233 trials.

Data Analysis 
Two independent reviewers analyzed the data obtained from each database and both agreed that the final list of trials fit the criteria for analysis. The lists of trials from each database, 68 trials from ClinicalTrials.gov and 233 trials from TrialTrove®, were cross-referenced using the NCT numbers as consistent trial identifiers between the two study sets. Duplicate trials (n=63) were eliminated resulting in a total of 238 unique clinical trials to evaluate.

The 238 clinical trials were then classified according to oncology indications and cancer types explored in the study, phases of the trial, and drug characteristics based on conjugated warhead. While many trials test multiple cancer types in parallel in the same study, each cancer type was tabulated independently.

Additional study details documented in peer-reviewed journal articles, abstracts presented at conferences, or other electronic sources by the study sponsors were used to obtain specific information on the drug and/or trial as needed.

The final set of studies included trials in all phases (I, II, III, and IV), indications (hematological malignancies and solid tumors), cancer types, and trial statuses (open, completed, and terminated).

3.0 Results 
The current clinical landscape of ADCs consists of 238 clinical trials which have been classified and analyzed by indication and cancer types, phases, and novel ADC characteristics including warheads conjugated to the mAb.

Table 1
Table 1

ADCs are being tested in both hematological malignancies (HM) and solid tumors (ST). A variety of cancer types are currently explored in clinical trials for both HMs (Table 1; Click to enlarge) and STs (Table 2; Click to enlarge) as well as unspecified cancer types or trials where both indications are studied concurrently (Table 3; Click to enlarge). ADCs are predominantly tested in HMs with 146 of the 238 clinical studies. Myelogenous leukemias, both acute and chronic, (n=64) are the leading cancer types tested in HMs followed by non-Hodgkin lymphoma (n=49).

Table 2
Table 2

The majority of the remaining trials are tested in STs, consisting of 89 of the 238 clinical studies. Breast cancer (n=39) is the leading ST cancer type where ADCs are tested followed by clinical trials open to various solid tumors (n=14), lung (n=12), ovarian (n=10) and prostate (n=10) cancers. A pair of trials (n=2) analyze cancer types in both HM and ST with concurrent testing in non-Hodgkin lymphoma (NHL) and renal cancer. Finally, one trial is being tested in unspecified cancer types.

Table 3
Table 3

The clinical trials are also spread throughout stages of development (Table 4; Click to enlarge) with most of the ADC trials being studied in phase II (n=83) and a number of drugs in their early stages of development in phase I (n=77). Clinical trials in later stage development in phase III (n=28) are also ongoing with four ADCs being tested: inotuzumab ozogamicin, gemtuzumab ozogamicin (Mylotarg®), trastuzumab emtansine (Kadcyla®), and brentuximab vedotin (Adcetris®). Kadcyla®and Adcetris® have already gained approval by the Food and Drug Administration (FDA). Kadcyla® was approved in 2013 for HER2-positive breast cancer and Adcetris® was approved in 2011 for Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL).

Table 4
Table 4

Of the 238 clinical trials, 47 unique ADCs are being tested ( Click to open Table 5) with the mAbs targeting a variety of cell surface proteins. There are 31 ADCs that have only been tested in STs, 11 ADCs only tested in HMs, and 5 ADCs that have been tested in both indications (Adcetris®, lorvotuzumab mertansine, MDX-1203, pinatuzumab vedotin, and vorsetuzumab mafodotin).

Screen Shot 2014-11-17 at 8.56.37 AM
Table 5

Of all the ADCs, Mylotarg® is the leading drug tested, consisting of 62 of 238 clinical trials. This is followed by Adcetris® and Kadcyla® with 47 and 34 of the 238 clinical trials, respectively.

Additionally, 11 unique cytotoxins are used in conjugation to the 47 ADCs (Figure 2; Clicl to enlarge). Predominantly, tubulin inhibitors Monomethyl Auristatin E (MMAE) (n=16), Monomethyl Auristatin F (MMAF) (n=6), Maytansinoid DM1 (DM1) (n=7), and Maytansinoid DM4 (DM4) (n=9) are the most common warheads. The tubulin inhibitors comprise 38 of the 47 ADCs. The 9 remaining ADCs are conjugated to calicheamicin (n=2), topoisomerase-I inhibitor/irinotecan metabolite (SN-38) (n=2), doxorubicin (n=2), duocarmycin (n=1), pyrrolobenzodiazepine (PBD) (n=1), and other or unknown cytotoxins (n=1).

Figure 2
Figure 2

4.0 Discussion 
It is clear that the scientific potential behind ADCs and the clinical need form this class of drugs in oncology are both substantial. Our goal with this review was to provide a complete visualization of the clinical landscape of ADCs that can foster the design of future research efforts and treatment options for patients with cancer. Several useful insights for clinical trial designers are readily apparent in this analysis.

First, there is a strong separation of ADC-based research in the clinic that tends to divide HM and ST indications into different trials. Studies tend to explore cancer types exclusively in either HM (n=146) or ST (n=89). Only three trials have combined exploration in both indications – two of which are specifically designed for NHL and renal cancer. This disparity may partly be due to the technical difficulties of mixing HM-based trial designs with ST-based trial designs. The biology of hematologic-based malignancies may be so different that there is little overlap of the ADC target in solid tumors. Additionally, the organization of regulatory agencies which separates HM and ST, particularly the FDA, may make such mixed studies extremely challenging to implement.

Second, the quantitative breakdown of HM versus ST trials is curious. While there are a numerically larger number of total clinical trials in HM versus ST (146 versus 89), a full 62 of the 146 HM trials involve just one ADC, Mylotarg®. Nearly half of the HM space is attributable to this ADC alone, irrespective of the other 15 ADCs being tested in HM. If you exclude Mylotarg® trials, there are nearly the same number of HM as ST trials, 84 versus 89.

Third, the ADC landscape reveals a considerable concentration of trial activity in the leukemias (77 of 146 HMs) and breast cancer (39 of 89 STs). There is clearly ample opportunity for development of ADCs in HMs and STs which are relatively unexplored, such as myeloproliferative disorders, melanoma, mesothelioma, or CNS, endometrial, or testicular cancers. All of these settings have two or fewer trials each and provide a potential opening for new ADCs, should appropriate targets be identified.

Fourth, the majority of clinical studies are currently in the early phase (I and II). There are a similar number of phase I trials in STs (n=40) compared to HMs (n=35). However, there are a significantly higher number of HM studies in the later stage (III). This may be biased by the initial early success of Mylotarg® in HM. This may also be due to the possibility of a higher failure rate of ST trials in early phases and the possibility that HMs are more tractable with ADCs compared to STs. Investigation of these possibilities is out of the scope of this review, but would be an interesting subject for future analyses.

Fifth, the current landscape of ADCs is obviously dominated by tubulin inhibitors as toxins, with 38 of the 47 ADCs conjugated to MMAE, MMAF, DM1, or DM4. This represents a potential opportunity for the use of cellular toxins with alternative mechanisms of action e.g. DNA-binding cytotoxins (calicheamicin, doxorubicin, duocarmycin, SN-38, and PBDs) when designing new ADCs for future studies.

In conclusion, the clinical landscape of ADCs provides a useful tool for all involved in oncology drug development. It will be exciting to see how this landscape evolves with the entry of new technologies, approaches, and targets.

Disclosures
Authors are employed by MedImmune, LLC. No funding was received in support of this article. 

Acknowledgements
The authors would like to express gratitude to David Jenkins, Jennifer McDevitt, and Mohammed Dar who have kindly reviewed the manuscript and provided valuable feedback. Additionally, we are grateful to Citeline for providing us with the permission to use their database in our analysis and thus, share our findings with the Journal.


August 1, 2014 | Sohayla Rostami, Ibrahim Qazi, PharmD, Robert Sikorski, MD, PhD | Corresponding Author Robert Sikorski, MD, PhD | doi: 10.14229/jadc.2014.8.1.001

Received June 30, 2014 | Accepted July 25, 2014 | Published online August 1, 2014

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