Radiation treatments for cancer often induce side effects such as fatigue, hair loss, nausea, and skin irritation because radiation affects all cells it passes through. To mitigate these side effects, several companies are developing radiolabeled antibody-drug conjugates (rADCs) to deliver radiation specifically to cancer cells. This approach aims to speed up treatment times and enable lower doses than traditional therapies.
The Promise of rADCs
Lana Janes, co-founder and chief operating officer of Abdera, noted that only two radiotherapeutics are currently approved: Novartis’ Pluvicto and Lutathera, which are radiolabeled small molecules for prostate cancer and neuroendocrine tumors, respectively. Big Pharma is investing heavily in biotechs with early-stage radiopharma assets to fill this gap, while other companies advance clinical development of rADCs.
ADCs, conceptualized as “magic bullets,” consist of antibodies tethered to radioisotopes. Chris Bardon, a co-managing partner of MPM BioImpact, stated that the future of ADCs involves experimenting with novel payloads. The radioisotopes, bound by chelators, target cancer cells by attaching to receptors on the cell surface. Once absorbed, the radioisotopes are released to exert their destructive effects, reducing side effects and accelerating treatment.
Clinical Development and Key Players
The first radioimmunotherapies were approved in the early 2000s for non-Hodgkin's lymphoma but were not preferred over chemotherapy. Since then, rADCs with actinium, lutetium, and iodine isotopes have been developed. Companies like Telix Pharmaceuticals, Actinium Pharmaceuticals, Convergent Therapeutics, Abdera Therapeutics, Bayer, and Fusion Pharmaceuticals are advancing clinical-stage rADC candidates for conditions like prostate and breast cancer.
Telix Pharmaceuticals has initiated a Phase III trial to evaluate its 177lutetium-labeled ADC candidate, TLX591, for metastatic castration-resistant prostate cancer. Interim Phase I results have shown that TLX591 reduces levels of prostate-specific antigen (PSA), an indicator of anticancer activity. Telix also has candidates for metastatic kidney cancer (177Lu), glioblastoma (131iodine), and bone marrow conditioning (90yttrium).
Convergent Therapeutics is also developing a lutetium-based prostate cancer candidate, CONV01-α, which has shown PSA reduction in Phase I/II trials. Shankar Vallabhajosula, vice president of radiopharmaceutical sciences at Convergent, highlighted the precision of modern drugs, which can quantify radioactive atoms per unit of antibody.
Abdera Therapeutics has developed a platform, ROVEr, for creating custom antibodies with optimized pharmacokinetics. Their lead candidate, ABD-147, a 225actinium-loaded biologic, has received FDA orphan drug designation and will be tested in Phase I trials for small cell lung cancer and large cell neuroendocrine carcinoma. Abdera aims to release radioactive particles inside the tumor without affecting healthy tissue.
Overcoming Hurdles
Working with radioactive materials presents unique challenges, including ensuring a steady supply of radioisotopes with short half-lives. Lana Janes is optimistic that manufacturing capacities will increase as more clinical trials are approved. The FDA requires human dosimetry information to understand radiation absorption in various tissues, which can be challenging to obtain.
Vallabhajosula noted that only 2-3% of an injected ADC reaches the target tissue, despite decades of engineering. Chris Bardon cautioned about picking winners before generating clinical data. However, Vallabhajosula emphasized that the clinical data indicates therapeutic effects with manageable toxicity, providing hope for the field.
Antibody-Drug Conjugates (ADCs) in Broader Cancer Treatment
ADCs are an emerging therapy in oncology, with over 260 ADCs currently being tested. The first ADC approved by the FDA was gemtuzumab ozogamicin in 2000 for CD33-positive acute myeloid leukemia. ADCs can deliver a “bystander effect,” which can be beneficial or increase off-target toxicity.
Aditya Bardia, MD, MPH, highlighted sacituzumab govitecan, trastuzumab deruxtecan, and datopotamab deruxtecan, all of which have shown superiority over chemotherapy in the metastatic setting. Other agents in development target LIV-1, HER3, ROR1, and CD166. Bardia anticipates that these treatments will gradually replace chemotherapy.
Domenica Lorusso, MD, PhD, noted that in ovarian cancer, FRα is an ideal biomarker due to its high expression. Toon Van Gorp, MD, added that TROP2 is a key target in cervical cancer, with sacituzumab govitecan and sacituzumab tirumotican being studied. Tisotumab vedotin has promising Phase 3 data in cervical cancer.
Challenges and Toxicities
Mechanisms of ADC resistance are still being understood. Bardia explained that switching between ADCs may work for patients resistant to the antibody but not for those resistant to the payload. Combining ADCs with other therapies, such as PARP inhibitors, may be synergistic.
Toxicities are a significant challenge due to the bystander effect. Ilaria Colombo, MD, MA, noted that a review of 169 trials found 600 different adverse events (AEs) for ADCs, with a treatment-related discontinuation rate of 13.2%. Specific ADCs have unique toxicities:
- Mirvetuximab soravtansine: Ocular toxicity due to FRα expression in the retina.
- Tisotumab vedotin: Ocular toxicity and bleeding.
- Trastuzumab deruxtecan: Interstitial lung disease.
- Datopotomab deruxtecan: Mucositis.
Colombo emphasized the need for a multidisciplinary approach to manage toxicities, similar to the approach used with immunotherapy.
