The Zenatek Tracking System (ZTS) ensures that packages are delivered safely, respecting the cold chain requirements and on schedule. The system can determine and trace all shipment routes, and sends immediate alerts if something unexpected happens to a package, notifying the user if, for example, a pallet’s seals have been tampered with or the goods are put at risk.

In the transportation of temperature sensitive pharmaceutical products, the respect of the cold chain is imperative; the Zenatek Tracking Service provides the opportunity to monitor continuously the temperature and the humidity inside the container. At the beginning of the trip, the user sets the temperature and humidity thresholds in the Zenatek web application, starting, in this way, the continuous monitoring of these parameters inside the container. In case of variance of temperature or humidity, our service will immediately notify, by email, the user about these anomalies and will also give the information about location where the anomalies happened. Therefore, the users will be in a position to take the necessary measures for managing the event in the proper way, such as calling those responsible for the transport, alerting the insurance company or the quality manager. Our service will place a notification by email informing that the parameters will be back within the expected levels.

The system informs users when container doors are opened and provides geocoded proof-of-delivery information to the recipient. This confirms that the shipment has reached its destination and there has been no unauthorised opening of container doors.

The system can also send notifications upon the return of containers to the shipping company’s yard, avoiding unjustified demurrages. ZTS informs clients if a container or pallet has turned on its side, capsized, or is involved in a destructive incident.

Pharmaceutical shipments can be monitored from departure to arrival at its destination anywhere in the world. Alerts are sent by Zenatek’s web-based system by email to any

The ZTS tracking device has an internal receiver that is compatible with GPS and GLONASS standards, and is also Galileo-ready to provide an accurate geographical position for a monitored shipment at any point. The system’s communication parameters, temperature and humidity can be remotely configured; even after a shipment has departed.

The ZTS will trigger alarms when a container’s internal temperature or humidity deviates from a predetermined level set by the client at the start of the forwarding. It also alerts the user when the temperature returns to the required set level.

At the end of the transportation, the device can be disposed, avoiding, in this way, expensive and time demanding reverse logistics practices

The ZTS design was based on strict cost control in order to develop container tracking devices at an affordable price without compromising the efficacy of what is needed by the end user; tracking and monitoring. ZTS monitors containers and assets in transit around the world, providing real-time information on possible tampering, temperature variances and location using GPS/GSM.

As a comprehensive, self-contained service, ZTS devices need not be retrieved at destination points because all traced route and shipment information is in the system and has already been transmitted. The devices may be used on a ‘one-way’ basis, this particular cost-saving feature makes it ideal for monitoring pharma cargo.

The battery life for a device sending six messages a day for twelve months. The number of daily reports can be altered according to the user’s requirements.
Alerts are sent by email to the user’s personal devices. The user is able to log in with an encrypted password and ID to view the cargo’s position and the notifications.

Through a multiple-mapping solution viewed on a web-based tracking portal, the position of the tracking device can be located within meters. Each unique user has access to the ZTS portal, enabling them to view the real-time location and where the cargo has been.

In under a few minutes, the container tracking device is attached to the internal face of the container door by three powerful magnets. No tools are needed for installation. Real-time logistics data is available as soon as the device has been installed.

The client may store documentation such as a packing list, bill of lading, and sanitary certificates in the web-based application. The information may be retrieved with a password from the client’s agent at the destination.

ZTS enables identification of chokepoints in the supply chain – where cargo is likely to be misplaced at terminals or delayed. Therefore, it also allows users to reduce safety stocks, which are the inventories that exceed normal needs and are used as a buffer against shipment delays.

Real-time information on what is happening with shipments and a reliable alarm system to report adverse incidents gives users control over the situation, and enables effective and prompt reaction for damage control if necessary; such as reshipping.

A

ntibody-drug conjugates (ADCs) hold the potential to change the nature of cancer treatment. Unlike classic chemotherapy – in which a drug is released into the body, killing cancer cells and healthy cells alike – ADCs enable the drug to be transported selectively to the site of action.

In essence, a cytotoxic drug is linked to an antibody, which homes in on a given protein (antigen) found only on tumour cells. Once the antibody has found its target, the tumour cell absorbs the molecule, which releases its toxic payload in the right place. At least in principle, this means killing the cancer while sparing healthy tissue, limiting side effects.

“In addition to being a classical therapeutic antibody, the antibody within ADCs needs to trigger internalisation into the cell upon target binding and maintain a high level of stability,” explains Marc-André Kasper, a researcher at the Leibniz-ForschungsInstitut für Molekulare Pharmakologie (FMP) in Berlin. “Meanwhile, the small molecule payload needs to be highly potent due to low concentrations of ADCs in cells.”

In recent years, there has been much discussion around ADCs, and there are more than 200 drugs of this kind at the clinical or preclinical stage. So far, six have been approved, including four in the past two years, and there are several others at the late stages of development.

One particularly exciting candidate is a molecule called DS-8201, which is being developed by AstraZeneca and Daiichi Sankyo. This drug is expected to become one of the biggest cancer biologics and could replace the breast cancer drug Herceptin.

While the concept is certainly promising, these drugs are often tricky to manufacture. As Kasper explains, ADCs combine the complexity of two worlds: small molecule chemistry and antibody biology. Then there’s a third factor, the linker that connects the two. This needs to be stable during circulation in the blood and yet capable of unloading the drug in tumour tissue.

“To be effective as a therapeutic for any indication, the ADC must be designed considering the appropriate combination of antibody, linker and payload,” he says. “It needs to take into account their individual and combined properties. Only then can we succeed in developing ADCs with a broad therapeutic window that generates added value for the patient.”

Up to now, the biggest issue with ADCs has been that they lose a high proportion of their toxic cargo in the bloodstream, rather than waiting to deposit it in the cancer cell. The culprit here is a faulty linker.

“The linker design has been a challenge in ADC development,” says Kasper. “Premature cleavage of the payload into the blood due to an unstable linker can cause severe side-effects and limits the therapeutic window of current ADCs.”

This is why the first generation of ADCs was unsuccessful in avoiding side effects. While the first ADC, Mylotarg, was approved as early as 2001, it was later withdrawn – the drug was being unloaded into patients’ bloodstreams at a sometimes fatally toxic dose. It was reapproved in 2017 at a lower recommended dosage.

Kasper, along with colleagues at the FMP and the Ludwig-Maximilians-Universität München (LMU), is working on solutions to this problem. In two recent papers published in Angewandte Chemie, his team discussed a new linker technology that could better stabilise the link between drug and antibody.

“We believe that linkage stability is one of the crucial aspects for developing the next generation of ADCs,” says Kasper. “In addition to that, previous research has shown that nonpolar linker-drug combinations limit the number of drug molecules that can be added to the antibody. So we aimed to increase the polarity of our linker system.”

Their technology is based on unsaturated phosphorus compounds (phosphonamidates), which can connect a given small molecule drug with the amino acid cysteine. Cysteine is naturally present in antibodies, albeit in small quantities. This means you can maintain a tight control over how the drug and antibody fuse together, and create a bond that is highly stable during systemic circulation.

“Cysteine modification is particularly interesting for the synthesis of ADCs, which has been previously demonstrated and applied to two of the approved ADCs on the market,” says Kasper. “Our technology allows the construction of ADCs with an acceptable homogeneity, starting from a native antibody, without any need for elaborative engineering. We have also developed a simple way to chemically install our compounds into very complex molecules in a chemoselective way. This is a process that hasn’t been described in the literature before.”

In order to test their method against others on the market, the researchers compared their technology with the approved ADC, Adcetris. Adcetris is a lymphoma drug, approved in 2017, which links the antibody brentuximab to the anticancer agent vedotin.

The team recreated this drug as precisely as possible, but replaced the drug’s existing maleimide linker with their own phosphonamidate linker. Then they applied the drug to blood serum to test its stability.

“We were able to demonstrate a drastic increase in stability with our technology,” says Kasper. “For Adcetris, we observed a payload loss of more than 75% after three days. In contrast, our linker lost less than 10% of the payload after seven days.”

From these results, the team hypothesised that a reduced dose of the redesigned ADC would be sufficient to treat mice with non-Hodgkin lymphoma.

“We were pleased to observe an increase in the median survival of the mice group treated with our redesigned phosphonamidate-linked Adcetris construct by more than two-fold compared to the group treated with Adcetris,” says Kasper.

Evidently, this technology could go a long way towards improving the safety and stability of ADCs.

“We have a lot of evidence that our method can solve some of the limitations that are currently associated with ADC treatment,” says Kasper. “It allows us to significantly reduce premature cleavage of the payload and reduce ADC dosing while still achieving a sufficient anti-tumor effect in mice. This means it has the potential to reduce side-effects and widen the therapeutic window of ADCs.”

Having demonstrated the technology in vivo, the researchers are now performing additional stability studies to improve their understanding of how it works.

“In addition, we are further optimising our linker system chemically. The rather unusual phosphorus-based structure still gives us a lot of room to play with and to implement new linker properties that are inconceivable with commonly applied linker systems,” says Kasper.

They have also founded a spin-out company, Tubulis, which will take the technology further, driving it towards market maturity.

“Tubulis is commercialising the technology and applying it to identify novel, uniquely matched antibody-drug combinations,” says Kasper. “Its chemical flexibility enables us to quickly identify perfectly matched ADCs that overcome current limitations in the field and deliver a better outcome for the patient.”