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Aspyrian’s Photoimmunotherapy based on the IRDye® 700 DX Platform Shows Efficacy in a Number of Studies

A novel, highly specific, anticancer therapy called near infrared (NIR) photoimmunotherapy (PIT) that uses IRDye® 700DX, a phthalocyanine dye also known as IR700, has shown efficacy in a number of studies and several preclinical models in mice. Experimental data confirms that the combinational effect of the mAb conjugated with IR700 (mAb-700DX) offers specific, targeted, delivery of the near-infrared photosensitizer and, as a result, provides rapid in vitro necrotic cell death as well as in vivo tumor shrinkage. Based on the experimental data suggesting clear survival benefit, investigators believe that this novel trial drug offers a potential promise as a new therapeutic agent. [1]

One of the unique characteristics of this novel mAb-700DX conjugate is that it only gains anticancer activity as a therapeutic agent when it is bound to the target cell membrane and is activated with a laser emitting 690 nm near infrared light (NIR) at the tumor site. When this occurs, the mAb-IR700 conjugate causes a rapid disruption of membrane integrity leading to rapid cell death that appears to follow necrotic processes rather than mechanisms of apoptosis. However, if the agent is not bound to the target cell, even upon NIR illumination, there are no discernible effects. As a result, this novel approach has minimal side effects.

In this article, the author discuss the development of the trial drug and how this cutting-edge technology may advance cancer treatment and improves the lives of patients.


1.0 Current treatment optioned are limited
When it comes to treating cancer, current cancer treatments are often limited by the harm they may cause to healthy, normal, non-cancerous cells. Although traditional chemotherapy has greatly improved survival in many patients with cancer, their limited specificity may lead to significant adverse events. To avoid damage caused by these adverse events, dose reductions, are required. In turn, this limits the effectiveness of these agents.

Hence, there is a significant unmet need for highly targeted and tumor specific treatments that maximize target-cell killing while minimizing damage to normal cells. For this reason there is a great interest in monoclonal antibodies (mAbs) conjugated with a payload such as a cytotoxic drug or radioisotope. These antibody-drug conjugates or ADCs have shown a great ability to target – and reach – specific cancer cells. Advances in engineering tumor specific monoclonal antibodies (IgG, IgM, chimeric, humanized antibodies to fully human antibodies) have, over the last two decades, greatly improved the potential of these unique drugs.

Although very promising, traditional antibody-drug conjugates have their limits as well. For example, first generation antibody-drug conjugates with suboptimal toxin load may have reduced efficacy while, on the other hand, highly cytotoxic ADCs are generally associated with increased toxicity. Premature cleavage of the payload from the antibody-linker complex, the inability of the conjugate to breach the cell wall and binding (albeit limited) to non-target sites or getting eliminated from the body early, may further reduce efficacy of the antibody-drug conjugate. Other complications may be caused by the instability of the linker between antibody and cytotoxic drug. To counter these issues, higher drug doses may be required, which, in turn, increases the cost of therapy and the potential adverse events. Factors such as these show that there is still ample room to advance antibody-drug conjugates through novel technologies.

2.0 A revolutionary approach
Aspyrian Pharmaceuticals, a privately funded, clinical stage biotechnology company based in San Diego, California, is developing, what they believe, a revolutionary way to use an antibody-drug conjugate in combination with near infrared light illumination (NIR). [2] Investigators working with Aspyrian Pharmaceuticals have developed a photoimmunotherapy (PIT) based on the IRDye 700DX platform which was originally invented by researchers at the U.S. National Institute of Health (NIH) and the National Cancer Institute (NCI). This novel technology consists of an antibody-drug conjugate that is regionally activated by a red-light emitting diode (690 nm) after it has recognized and is attached to cancer cells. The PIT drug consists of a monoclonal antibody conjugated to the photosensitizer phthalocyanine dye IRDye® 700DX (NHS Ester). [3]

In anticipation of evaluating this technology in clinical trials, Aspyrian Therapeutics Inc. enlisted the support of Goodwin Biotechnology, Inc., a biological Contract Development and Manufacturing Organization (CDMO) that specializes in bioprocess development and GMP manufacturing of biopharmaceuticals utilizing Mammalian Cell Culture expression systems and Bioconjugation technologies, to optimize and scale up the process, and then perform cGMP manufacturing of their unique antibody-drug conjugate.

3.0 Unique Characteristics
In contrast to other ADCs, antibody-photosensitizer conjugates such as the mAb-IR700 are largely independent of the need for internalization.

Furthermore, the conjugate technology can be applied to many antibodies without affecting the binding or the functionality of the antibody. Examples of mAb-IR700 conjugates include trastuzumab (anti-HER2), panitumumab and cetuximab (targeting EGFR) as well as an anti-CD44 monoclonal antibody designed to treat primary and secondary triple-negative breast cancer, and others. [4]. As a result, it is possible to develop a host of mAb-IR700 complexes designed target a variety of cancers.

Figure 1.0 Effects on Photoimmunotherapy on cancer cell membrane integrity. The left panel shows the phase contrast image of cancer cells prior to treatment. The middle panel shows the fluorescence detection of the antibody conjugate with IRDye 700DX bound to the cell membrane, and the right panel shows the phase contrast image of the cells after light illumination. Note that the cell integrity has been severely damaged after treatment (adapted from Mitsunaga M et al., BMC Cancer. 2012 Aug 8;12:345).
Figure 1.0 Effects on Photoimmunotherapy on cancer cell membrane integrity. The left panel shows the phase contrast image of cancer cells prior to treatment. The middle panel shows the fluorescence detection of the antibody conjugate with IRDye 700DX bound to the cell membrane, and the right panel shows the phase contrast image of the cells after light illumination. Note that the cell integrity has been severely damaged after treatment (adapted from Mitsunaga M et al., BMC Cancer. 2012 Aug 8;12:345 – Source: Aspyrian Therapeutics, Inc.)

Finally, another unique characteristics observed in preclinical animal (mouse) models is that this photosensitizing compound, when distributed throughout the body, does not do harm unless the dye binds to a cell and an intense infrared light is applied to the prodrug, which is then activated.

In pre-clinical research, single NIR light irradiation was effective without significant side effects [5] Following exposure with NIR, target-selective necrotic cell death was observed in vitro [6] while progressive tumor shrinkage in vivo, was observed 3 – 4 days after a NIR-PIT – even after a single administration of mAb-IR700 and a single exposure with near infrared light illumination.[5][6]

Photoimmunotherapy (PIT), based on the novel trial drug mAb- IR700, is tumor-specific and has demonstrated specific binding to target receptors on the cell membrane, which is then followed by gradual internalization into endolysosomal compartments. Initial pre-clinical studies seem to suggest that this trial drug may potentially deliver very rapid and potent cancer killing effects while sparing healthy tissue adjacent to the tumor. [6] [7]

While other novel therapies may be more effective in tumor targeting with reduced adverse events, the majority offer, so far, only limited success. Combining conventional, targeted, cancer therapies with activating physical energy, like light or heat – such as in the case of NIR-PIT’s like mAb-IR700 – may be a potential method of improving therapeutic selectivity. [6] [8][9]

Chief Scientific Officer, Aspyrian Therapeutics Inc
Photo 1.0 Miguel Garcia-Guzman, PhD, President and Chief Scientific Officer, Aspyrian Therapeutics Inc.

4.0 From mAb-700DX to RM-1929
In an interview with Miguel Garcia-Guzman, PhD, President and Chief Scientific Officer of Aspyrian Therapeutics (Photo 1.0) and Muctarr Sesay, PhD, Chief Scientific Officer and Vice President of Bioconjugation at Goodwin Biotechnology, we discussed the development of RM-1929 and the reasons why NIR-PIT may be an important breakthrough in ADC-based cancer treatment. Garcia-Guzman and Sesay addressed some of the questions that physicians and researchers may have about this new technology and they shared with us how NIR-PIT is different from current ADC technology, and how these key differences may lead to a new, more effective and better tolerated cancer treatment option.

5.0 Platform technology
Aspyrian Therapeutics, which holds the patent to the exclusive use of the IRDye 700DX platform from Li-COR (Lincoln, Nebraska), is currently investigating RM-1929 in a Phase I clinical trial for the treatment of recurrent head and neck cancer.

Figure 2.0 Cancer Killing is mediated by the activation of the antibody conjugate bound to cancer cells with Laser Illumination of the tumor. Photoimmunotherapy with IRDye 700Dx induces cancer killing following a two-step process: (I) systemic administration of the antibody conjugate with IRDye 700Dx that targets antigens at the surface of the cancer cells leading to tumor binding and selective accumulation of the drug in the tumor; (II) following binding of the antibody conjugate to the cancer cells, laser-mediated illumination with light in the near-infrared range (690 nm) leads to activation of the dug conjugate and rapid selective destruction of the cancer cells that are bound to the antibody. Unbound drug is inert, even upon light illumination, and consequently the treatment is highly cancer specific sparing damage to healthy tissue around the tumor. (Source: Aspyrian Therapeutics, Inc.)

This trial drug is based on the IRDye 700DX platform invented by Histaka Kobayashi, MD, PhD., and Peter Choyke MD, at the Center of Cancer Research (CCR) Molecular Imaging Program of the National Cancer Institute. Since the early days of this development, this technology has shown promising results in a number of in vitro and in vivo laboratory settings.

In their initial studies these researchers showed that when the mAb-IR700-cancer-cell-complex was irradiated with near-infrared (NIR) light cancer cells died rapidly but that Infrared light alone or mAbIR700-conjugate alone did not damage normal cells. Furthermore, in treating breast cancer tumors implanted in mice with mAbIR700-conjugate and near-IR light they observed that PIT could result in massive and immediate cancer cell death and prolonged survival.

6.0 Bioluminescence imaging
Bioluminescence imaging or BLI, is a non-invasive imaging modality used in pre-clinical oncology research. This imaging modality involves the generation of light by luciferase-expressing cells in vivo following administration of a substrate. This relatively new technique allows a variety of tumor-associated properties to be visualized dynamically in living models. Using BLI, investigators were able to analyze disease processes at the molecular level. BLI is also an efficient way to measure tumor progression and metastasis. [6][10]

Although tumor sizes did not change after the PIT treatment given in initial studies with EGFR target-specific mAb-IR700 conducted by investigators at Aspyrian Therapeutics, the BLI signals decreased by >95% immediately after PIT. Additionally, BLI revealed that when the tumors were treated with the prodrug, no pharmacological activity occurred without or before irradiation. The fact that the drug was inactive without irradiation reveals its potential for creating a very regionally specific treatment, since the near infrared laser is focused only on the tumor area. [11][12]

Figure 2.0 Anticancer effects mediated by Photoimmunotherapy with IRDye 700Dx in vivo are rapid and highly effective. Treatment of both subcutaneous and orthotopic xenografts shows that within hours post light illumination the tumor is effectively destroyed. Experimental data has shown that the effects are highly cancer specific so that damage to healthy surrounding tissues are spared. This figure shows the anticancer response upon one round of treatment in an xenograft model implanted with two orthotopic breast cancer tumors, one serving as control and a second one treated using Photoimmunotherapy with IRDye 700Dx.
Figure 3.0 Anticancer effects mediated by Photoimmunotherapy with IRDye 700Dx in vivo are rapid and highly effective. Treatment of both subcutaneous and orthotopic xenografts shows that within hours post light illumination the tumor is effectively destroyed. Experimental data has shown that the effects are highly cancer specific so that damage to healthy surrounding tissues are spared.  This figure shows the anticancer response upon one round of treatment in an xenograft model implanted with two orthotopic breast cancer tumors, one serving as control and a second one treated using Photoimmunotherapy with IRDye 700Dx. The upper panels of full body fluorescence imaging (FLI) detecting the accumulation of the antibody-IRDye 700DX conjugate at the two tumors. The upper tumor (right tumor in the mice) is then treated with 690 nm light illumination while the lower tumor (left in the mice) is not illuminated and serves as control). Treatment triggers rapid effects on tumor integrity as visualized with bioluminescence imaging (BLI). The treated tumor (upper tumor in the image) is completely destroyed while the untreated tumor (lower tumor in the image) is unaffected (adapted from Mitsunaga M et al., BMC Cancer. 2012 Aug 8;12:345. Source: Aspyrian Therapeutics, Inc.

In a separate study on mice implanted with pancreatic cancer tumors, PIT resulted in a significant reduction in tumor size and, once again, cell death was seen immediately after irradiation.

“In this case, immediate means that you can actually monitor instantaneously that you are affecting the cancer in vivo and in vitro,” noted Garcia-Guzman. Again, no significant effect was seen without both tumor attachment of the ADC and irradiation with light thereafter. [11]

7.0 Clinical Trials
The results of these initial studies sparked the interest of researchers at Aspyrian Therapeutics working in conjunction with their colleagues at Goodwin Biotechnology to manufacture the product candidate. Based on the investigational data, these researchers have developed the RM-1929, an antibody-drug conjugate, which, they expect, will show promising results in a current, ongoing, Phase I clinical trial (NCT02422979). The trial drug is being investigated for the treatment of patients with head and neck cancer (HNC) that – according to the patient’s physicians – cannot be satisfactorily treated with surgery, radiation or platinum chemotherapy.

In April 2015 the US Food and Drug Administration (FDA) accepted Aspyrian’s first Investigational New Drug (IND) application allowing the company to initiate clinical studies.

In this first of its kind trial, investigators are trying to establish the Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD) of RM-1929, whichever is lowest, determine the adverse event profile for each dose, and assess the safety of the combination of the drug with low energy localized light irradiation (NIR) which includes skin photosafety (sunburn) testing designated to determine skin Minimal Erythema Dose (MED).

8.0 Mechanism of Action
RM-1929 consists of the monoclonal antibody cetuximab, designed to target EGFR, conjugated to the payload drug IR700 by a covalently bonded linker.

Because EGFR is highly expressed in squamous cell carcinomas of the head and neck, it is expected that systemic administration of RM-1929 will lead to tumor accumulation of RM-1929 and binding to EGFR expressed at cancer cells.

Following administration of RM-1929, subsequent light irradiation (NIR) should induce rapid tumor destruction of recurrent head and neck carcinoma (HNC) and provide an effective therapy to manage the disease.

Just as in the case of the platform trial drug, preclinical pharmacology demonstrated that light-induced activation of RM-1929 elicits rapid tumor destruction of human cancer xenografts implanted in mice, thus enhancing progression-free survival and overall survival with a better Quality of Life (QoL) than when using existing current Standard of Care (SOC) approaches.

As shown, two factors need to be met before the inert prodrug is able to have any pharmacological activity or what is called a “precision dual-targeting cancer treatment” effect. First, the monoclonal antibody must recognize and bind to tumor cells by targeting epidermal growth factor receptors (EGFR) present on the tumor cell surfaces. Second, laser-mediated illumination with light in the near-infrared range is only ‘activating’ on those mAbs that are bound to the tumor cells.

9.0 Adverse Events
Since both of these factors must be met for the drug to activate, there is a potential for more specific targeting of tumors. This means that activation of IR700 can be kept at the tumor site and systemic toxicity of the payload may be avoided. “If it is not bound, even if you irradiate with NIR light, there is basically no effect,” noted Garcia-Guzman. “What this approach provides is very exquisite cancer specificity.” [12]

In mAb-IR700-conjugates or such as with RM-1929, the fact that the drug remains inert before irradiation means there is a lesser degree of toxicity on healthy cells. In contrast, in traditional ADCs, the cytotoxic molecule or payload is not inert. Even though antibody recognition is able to target tumors, the drug may still be activated in healthy, surrounding tissue. Furthermore, conventional photodynamic therapy (PDT) photosensitizers lack tumor-specificity. In photoimmunotherapy (PIT), “Even if the antigen is bound to another tissue or organ somewhere else in the body,” noted Garcia-Guzman, “You only irradiate the tumor, and therefore, there is no pharmacologic trigger required to activate the dye.” And, since the payload drug will remain inert until activation by irradiation, photoimmunotherapy is very safe from a systemic prospective. [13]

10.0 Linker
Using a light source for activation means there is no need for degradation of a linker. This contrasts with currently available ADCs as well as most ADCs in clinical trials who require linkers to be optimized in order to degrade in tumor cells and release the active cytotoxin or payload. However, with PIT, the mechanical activation – by heat or light – of the drug means that cellular degradation of the linker is not necessary. As a result, the drug can be activated in as little as 24 hours! Emphasizing this crucial difference, Garcia-Guzman made clear that this means that it is not as important whether or not the parts of the ADC remain conjugated.

“From the pharmacological point of view, it doesn’t make a difference whether or not the antibody remains on the surface bound to the antigen,” he said. “There is very little difference in the effect of IR700 when the linker remains intact as opposed to when it is cleaved. Because the light is only concentrated on the tumor site, the drug becomes active affects the tumor cells.” An important additional characteristic of the trial drug is that the infrared light used to activate the payload is completely safe in humans. [14].

Photo 2.0 Muctarr Sesay, PhD, Chief Scientific Officer and Vice President of Bioconjugation at Goodwin Biotechnology, Inc.

11.0 Impact on Drug Resistance
“One major issue with traditional ADCs is a limited potency because of cellular resistance,” noted Goodwin Biotechnology’s Muctarr Sesay (Photo 2.0). “Conventional ADCs rely on cellular mechanisms for activation. Therefore, cells can adapt and become resistant to the drug after being exposed to it more than once. [15] [16] Since RM-1929 is activated by a physical process as opposed to reliant on cellular mechanisms, resistance is not a problem.”

“PIT will, in most circumstances, only need to be administered in a single dose,” Garcia-Guzman adds. “In fact, another unique characteristic of this application,” he points out, “Is that antibodies that may have not yet been activated by the initial light treatment may re-accumulate in the remaining tumor cells. “When that happens, you can actually follow-up with a new light treatment and basically have an even more extensive anticancer killing effect,” Guzman noted. [17]

12.0 Potential for Combination Therapy
“As shown in a number of preclinical trials, the payload molecule IRDye (IR700) has the potential to be attached to several different monoclonal antibodies,” Sesay said. “This makes the targeting of various different cancers a real possibility.”

Depending on the results of the RM-1929 trial, there are hopes for PIT potential as first line therapy. “If we can prove that this translates into the clinic, and the safety and cancer specificity is really as high as predicted,” Garcia-Guzman confirms, “then we can expect that this technology when combined with other monoclonal antibodies may indeed become an alternative to front line therapies for a number of specific cancer types.”

In addition to being used as an individual therapy, there is potential for combining PIT with surgical resection and chemotherapy. The use of PIT in conjunction with other treatments is expected to increase the anticancer response with a significant reduction of tumor burden and lower the chances of tumor recurrence after standard treatments.

13.0 Bright Light Surgery
A study on PIT in combination with bright light surgery (BLS) showed significantly less tumor recurrence in mice treated with this combination, in comparison to those that received only BLS. With BLS, even after a tumor is removed, recurrence is not uncommon. Garcia-Guzman noted that after BLS, the use of PIT can eradicate any remaining micro-tumors that remain in the body after surgery. That’s why the clinical development of PIT will include evaluation of its activity in combination with surgery and other cancer modalities, as well as its effect in preventing recurrence. [18]

Garcia-Guzman clarified that the goal of PIT is not to try to replace any current cancer modalities, but instead provide a novel approach to cancer treatment on its own or when used in combination with existing treatments. “We see this technology being treated in conjunction with other cancer modalities to maximize anticancer activity,” Garcia-Guzman said.

Researchers at Aspyrian Therapeutics are confident that near infrared (NIR) photoimmunotherapy (PIT) with mAb-IR700 may lead to a novel, and widely applicable therapeutic platform.


Last editorial review September 29, 2015

This article is researched and Written by Sonia Portillo based on interviews with

  • Miguel Garcia-Guzman, Ph.D., President and Chief Scientific Officer at Aspyrian Therapeutics, Inc. and
  • Muctarr Sesay, PhD, Chief Scientific Officer and Vice President of Bioconjugation at Goodwin Biotechnology, Inc.

Feature image Courtesy: © Aspyrian Therapeutics, Inc. 11189 Sorrento Valley Rd. #104, San Diego, CA, 92121, USA.  Courtesy Photo 1.o: © El Mundo – Unidad Editorial Información General S.L.U. Avenida de San Luis, 25, 28033 Madrid, Spain. Courtesy Photo 2.0:  © Goodwin Biotechnology, Inc. 1850 NW 69th Ave #4, Plantation, FL 33313, USA.  All images used with permission.

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The Clinical Landscape of Antibody-drug Conjugates

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).

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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This work is published by InPress Media Group, LLC (The Clinical Landscape of Antibody-drug Conjugates by Sohayla Rostami, Ibrahim Qazi, PharmD, Robert Sikorski, MD, PhD) is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Non-commercial uses of the work are permitted without any further permission from InPress Media Group, LLC, provided the work is properly attributed. Permissions beyond the scope of this license may be available at adcreview.com/about-us/permission.

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