New ADC Technologies: Deadlier For Tumors, Safer For Patients

By Ed Miseta, Chief Editor, Clinical Leader

The concept of ADCs (antibody-drug conjugates) has been around for more than 20 years. The thinking behind them is that on the surface of cancerous cells there are overexpressed proteins (antigens). According to Anna Protopapas, president and CEO of Mersana Therapeutics, the “circuitry” around cancer cells goes haywire, causing the antigens to appear. ADCs attempt to use those antigens to attack the tumor cells.

“The hope is we can design an antibody that will only bind to those cancer-specific proteins,” says Protopapas. “The antibody carries a cytotoxic drug that penetrates the cancerous cell. Once there, it will release the cytotoxic drug, causing the captured cell to die.”

This seems, on the surface, to be a pretty simple idea. But getting to that final result has taken a good amount of time and research. Seattle Genetics and ImmunoGen pioneered the approach, and currently have products on the market. Kadcyla uses the ImmunoGen technology and is currently in its second generation while ADCETRIS uses the Seattle Genetics approach. ADCETRIS currently has sales of more than $250 million. It is also being used in trials for treatment of cutaneous T-cell lymphoma and in trials in combination with Bristol-Myers Squibb’s Opdivo for the treatment of Hodgkin lymphoma. Kadcyla, Roche’s late-stage breast cancer offering, has been shown to shrink tumors, slow disease progression, and extend life. Roche is currently spending $200 million to build a new manufacturing facility in Basel, Switzerland, to produce drugs like Kadcyla and some of the 25 ADCs in its pipeline.

Protopapas is no stranger to the technology. She worked on ADCs at Millennium and then Takeda (which sells ADCETRIS outside the U.S.) for almost two decades before joining Mersana. Although she saw some of the early challenges of those first-generation technologies, she was also able to witness some of the successes. She personally had the opportunity to meet patients who experienced incredible recoveries when using ADCETRIS. She believes the experience helped her to understand and appreciate the benefits of ADCs.

ADCs have improved and matured over the last 20 years, becoming more of an established cancer therapy. Protopapas notes that in that time, around 80 ADCs have made it into clinical trials. Currently there are approximately 60 ADCs in clinical studies.

BIGGER PAYLOADS BRING INCREASED TOXICITY
Since ADCs first hit the market, researchers have attempted to increase their efficacy by going to superpotent payloads including a highly potent cytotoxic agent called pyrrolobenzodiazepine (PBD). PBDs have been effective at delivering more potent payloads to tumor sites. Several ADCs using PBDs have made it into clinics recently, which Protopapas lauds as a major advancement in the field.

Of course, more potent payloads are also more toxic to surrounding tissues. To solve that problem, Mersana pioneered a new approach using a proprietary platform (Fleximer) that delivers a higher amount of payload to the cancer cells without harming healthy tissues.

“There is certainly a real concern surrounding these bigger payloads,” adds Protopapas. “With higher levels of agents you have to worry about issues occurring when the payload is released after the tumor is killed. We are still very early in the review process, and unfortunately, we do not have a lot of clinical data. But the clinical data we do have demonstrates there is reason to be concerned with these super-potent payloads.” (Editor’s note: A December 27, 2016, press release from Seattle Genetics notes an FDA clinical hold had been placed on several early-stage trials of its ADC SGNCD33A, designed to be stable in the blood stream and release a potent agent upon internalization into cells.)

Protopapas believes Mersana has improved the approach to ADCs in two very important ways. In the traditional ADC approach pioneered by ImmunoGen and Seattle Genetics, the cytotoxic payload is attached directly to the antibody. She notes there is data published by both companies and academic groups showing the maximum molecules (cytotoxics) per antibody to be three to four. Mersana’s technology can add four to five times that payload to a given antibody, delivering as many as 15 to 20 payloads.

“As you can imagine, the more payload you can deliver to the site of the tumor, the more efficacious you can be,” she states. “We now have data showing we can cause complete tumor regression in preclinical models using our drug. That is to say, we have no detectable tumor at the end of the study. And, to the best of my knowledge, no other company is taking the same approach.”

"From a clinical development standpoint, I don’t think the path to development and approval of ADCs will really be that different from the path of approval of any oncology drug."

Anna Protopapas
President & CEO, Mersana Therapeutics

KILLS CANCER, SAVES HEALTHY TISSUES
The second way Mersana has improved the ADC approach may be the more important one. Although the company is delivering a greater payload, it uses what Protopapas describes as “very elegant medicinal chemistry” to minimize its impact on the patient.

“In any ADC, the payload released is toxic so as to kill the tumor,” says Protopapas. “Unfortunately, that toxic payload also has the ability to permeate adjacent cells. In the ADC field we call this the ‘bystander effect.’ We do not want that payload to have the ability to travel to healthy tissues. The cytotoxic drug we use is extremely potent when released into the cancer cell, but it then becomes trapped in the cell and gets metabolized into a form that is a lot less toxic. It essentially destroys the cancer cell and then detoxifies itself, making it a lot more tolerable to patients.”

The payload gets metabolized into a form that cannot penetrate the cell membrane. It enters the cancer cell and travels to adjacent cancer cells, effectively destroying them. But when the cancer cells are destroyed and released into circulation, the payload released cannot penetrate adjacent healthy tissues.

The traditional approach to ADCs had the payload attached to the antibody via a linker. The stability of the linker is important because you want the drug conjugate to be very stable while in circulation and to eventually release the payload once it enters the target cell. With Mersana’s technology, there is a bond between the payload and the antibody, which is called a Fleximer. The Fleximer is a biodegradable polymer, and the payload is attached to the polymer.

ADCS READY TO ADVANCE TO PHASE 2/3
Protopapas notes there are three or four ADCs currently in Phase 3 trials, 16 that are in Phase 2, and approximately 40 that are in Phase 1. In pharma, outsourcing is the current method of conducting trials, and companies now work with sites across the country and around the world. It seems the movement of many of those 40 ADCs from Phase 1 to Phase 2 or 3 could be a significant event for the industry. She believes sponsors, sites, and CROs will be ready for that migration.

“From a clinical development standpoint, I don’t think the path to development and approval of ADCs will really be that different from the path of approval of any oncology drug,” states Protopapas. “The FDA would certainly look at the safety and efficacy of the drugs and make a judgment based on the risk/benefit in a similar way they would for any other oncology drug.”

She notes the area where ADCs might be different from other oncology treatments is with the manufacturing vendors. Although the payload is similar to the small molecule payload, putting the antibody and payload together is what makes ADCs unique. There is a large number of global suppliers with expertise doing that, and Protopapas believes they will be ready to support the growing need.

When it comes to sites and CROs, she also does not believe more ADCs in trials will be a challenge. Patient recruitment channels already in place will enable them to get the volunteers they need. In fact, Protopapas believes new technologies and medications, including ADCs, will help to partially alleviate the patient recruitment challenge that has plagued pharma.