rADCs Could Take Cancer Treatment ‘Magic Bullet’ to a New Level

Radiation treatments for cancer often come with side effects like fatigue, hair loss, nausea and skin irritation because as the waves traverse through the body, they affect all the cells they pass on the way to the cancer cells. Despite this, radiation is still used because it is simply good at treating certain cancers. However, several companies are looking to radiolabeled antibody-drug conjugates (rADCs) to bypass these side effects and deliver radiation only to cancer cells without affecting healthy ones, speed up treatment times and enable lower doses than traditional therapies.

“We’re still in a position where there have been only two radiotherapeutics approved right now in this renaissance of radiopharmaceuticals,” said Lana Janes, co-founder and chief operating officer of rADC developer Abdera. Those two are Novartis’ Pluvicto and Lutathera, radiolabeled small molecules that were approved to treat specific types of prostate cancer and neuroendocrine tumor, respectively. Keen to fill this gap, Big Pharma is dropping billions to gobble up biotechs with early-stage radiopharma assets, while still other companies are advancing clinical development of rADCs, a category of radioimmunotherapies that has yet to see its first FDA approval.

ADCs have been tested as cancer therapeutics for decades, spurred by the magic bullet concept proposed in the early 1900s. ADCs are essentially antibodies tethered to a drug of choice, in this case radioisotopes. “The future of ADCs is actually experimenting with novel payloads,” said Chris Bardon, a co-managing partner of MPM BioImpact.

Bound by chelators, the radioisotopes home in on cancer or tumor cells thanks to antibodies, which attach to receptors on the cell surface. Once absorbed by the cells, the radioisotopes are released from the chelators and are free to exert their destructive powers. By releasing the radioisotope only in the target cells and nowhere else, drug developers hope that rADCs will markedly ameliorate the side effects associated with traditional radiotherapy and hasten treatment.

The first radioimmunotherapies for cancer treatment were approved in the early 2000s for non-Hodgkins lymphoma, but were not preferred over existing chemotherapy regimens. Since then, however, many rADCs bearing actinium, lutetium and iodine isotopes, among others, have been developed and tested in clinical trials. Companies working on these drugs include Telix Pharmaceuticals, Actinium Pharmaceuticals, Convergent Therapeutics, Abdera Therapeutics, Bayer and Fusion Pharmaceuticals, all of which are advancing clinical-stage rADC candidates in conditions like prostate and breast cancer. “We really see this as an emerging modality that’s in the armament of an oncologist’s toolbox,” Janes said.

Last year, Telix began a Phase III trial to assess the risks and benefits of its leading ¹⁷⁷lutetium-labelled ADC candidate for metastatic castration-resistant prostate cancer. A second is in the works. The drug, called TLX591, has an antibody that targets prostate-specific membrane antigen (PSMA), a marker of prostate cancer cells. By bringing radioactive lutetium directly to the cancer cells, TLX591 has been shown in interim Phase I results to reduce levels of prostate-specific antigen (PSA) in patients, an indicator of anticancer activity. The Phase III trials are set to wrap up in 2028, and Telix has other candidates in the pipeline for metastatic kidney cancer (¹⁷⁷Lu), glioblastoma (¹³¹iodine) and bone marrow conditioning (⁹⁰yttrium).

The antibody that eventually became part of TLX591 was first discovered by Neil Bander, an emeritus professor of urology at Weill Cornell University and one of the founders of Convergent Therapeutics, another prominent player in the rADC field. Convergent’s own actinium-based prostate cancer candidate, CONV01-α, also reduced PSA levels in Phase I/II trials. CONV01-α uses the same PSMA-targeted antibody as TLX591, although Telix claims to have modified its version, said Shankar Vallabhajosula, vice president of radiopharmaceutical sciences at Convergent and emeritus professor of radiochemistry and radiopharmacy at Weill Cornell.

Vallabhajosula was part of the initial efforts to figure out the therapeutic potential of the antibody beginning in the late 1990s. Having been in the field of radiochemistry for nearly 50 years, Vallabhajosula appreciates the precision of today’s drugs, which can be quantified down to the number of radioactive atoms per unit of antibody. This precision, alongside a readily available and well-characterized bank of chelating agents, has fueled the surge in rADCs, he said.

Taking a different tack is Abdera Therapeutics, which has developed a platform for making custom antibodies that carry a desired payload. A key concern that comes with using biologics is optimizing the half-life of the targeting molecule, which can be tricky, said Janes. If a drug hangs around in the body for too long, it can cause problems like bone marrow toxicity and kidney load. But if it degrades too quickly, it may not kill enough tumor cells. To solve this puzzle, Abdera developed a platform called ROVEr that fine-tunes an antibody’s pharmacokinetics. Then, using a prepared library of linkers and chelators, the radioactive payload can be attached. By tweaking the biologic and pairing it with the right radioactive isotope, Abdera hopes to “get enough of those individual [radioactive] particles releasing inside of the tumor without them also decaying and being released near the healthy tissue,” Janes explained. Its lead candidate, a ²²⁵actinium-loaded biologic called ABD-147, was recently granted orphan drug designation by the FDA and will be tested in Phase I trials for small cell lung cancer and large cell neuroendocrine carcinoma.

Despite the precision and promise of rADCs, working with radioactive materials comes with unique challenges. A key issue is ensuring a steady and reliable supply of radioactive material, which is a problem given usually short half-lives that range from days (actinium) to mere hours (lead). As a result of this time constraint, radioisotopes are either made or sourced on demand and cannot be stored for long even after conjugating them with the antibodies, Janes explained. She is optimistic, however, that capacities will increase as more clinical trials are approved.

“The number of contract manufacturers who are able to manufacture these drugs and provide them to clinical sites in time has increased, as well as the number of contract research organizations that are capable of working with these kinds of hot products,” Janes told BioSpace.

Once an rADC is made, there is the matter of clinical trials and regulatory approvals. The FDA has a well-established pipeline for radiotherapeutic agents but often requires human dosimetry informationto understand how much radiation is absorbed in various tissues of the body, Vallabhajosula said, nothing that results from animal models may not translate to people. “Patients are not comfortable if you use them as guinea pigs just for dosimetry purposes,” he said.

On the patient end, an enduring challenge has been the attrition rate of an ADC once it enters the body. Notwithstanding decades of engineering and fine-tuning of antibodies, chelators and linkers, no more than 2–3% of an injected ADC reaches the target tissue, Vallabhajousula said. Bardon stressed this issue, cautioning, “That’s part of the problem of picking winners before we generate clinical data.”

Even so, patients are responding to experimental treatments and companies are forging ahead. “The clinical data is telling us things are working, producing the therapeutic effect, and the toxicity is not outrageous. That’s what is giving the hope,” Vallabhajosula said. Complemented by platforms from companies like Abdera and Actinium Pharmaceuticals, researchers can be hopeful of overcoming old obstacles, Janes said. “We’re all rooting for each other’s success.”