Radioligand therapy (RLT) is experiencing a dramatic renaissance in modern medicine. The recent approvals of Xofigo, Lutathera, and Pluvicto have transformed this once-niche field into an area of intense scientific and commercial interest. Successful RLT with an optimal therapeutic index requires the careful application of several key principles. This presentation will explore the fundamental elements necessary for developing effective and safe radioligand therapies.

In contrast to Prostate-Specific Membrane Antigen (PSMA), Prostatic Acid Phosphatase (ACP3) is virtually absent in healthy organs but highly expressed in prostate cancer. We used DNA-encoded chemical libraries to identify highly potent ACP3 ligands which selectively accumulated in ACP3-positive tumor lesions in mice—with curative effects at low and well-tolerated 177Lu doses. Our clincial candidate, OncoACP3, may overcome current limits of PSMA-based ligands for pharmacodelivery applications in prostate cancer patients.

PSMA is a validated cancer target in metastatic CRPC. Use of an alpha emitter as a radionuclide and a high affinity monoclonal antibody offers the promise of improved potency and accuracy of PSMA-targeted therapy. 225Ac-J591 has been evaluated for safety and efficacy in academic investigator-initiated trials with promising results. CONVERGE-01 is an industry-sponsored study of CONV01-alpha (225Ac-J591) in patients with progressive PSMA PET-positive CRPC. Enrollment began in August 2024.

Telix is a therapeutic radiopharmaceutical company, committed to precision oncology. Our theranostic pipeline focuses on critical unmet medical need in urologic oncology, neuro-oncology, musculoskeletal oncology, and hematology. For each target we develop a radiodiagnostic imaging agent, along with a therapeutic candidate, including beta and alpha therapies. Our objective is to bring to market first-in-class or best-in-class theranostics by selecting isotopes and targeting agents that are tailored to each clinical application.

Fibroblast Activation Protein has emerged as a promising target of radiopharmaceuticals in imaging and therapy. Here we discuss the current state of FAP targeting for imaging in gastrointestinal cancers. In addition, we will highlight the latest clinical development and regulatory efforts with [18F]FAPI-74 in the United States.

Investigational approaches to pretargeted radioimmunotherapy (PRIT) are designed to optimize the delivery of cytotoxic radiation to tumors, whilst limiting exposure to normal “off-target” tissues. Here, we’ll present the scientific rationale and preclinical evidence supporting the clinical development of self-assembling and disassembling bispecific fusion proteins used in two-step PRIT for the treatment of solid and hematological malignancies.

Radioligand therapy is an emerging tool in cancer treatment with recently demonstrated medical and commercial value. A challenge, however, is the generation of efficient tumor-targeting radionuclide carriers with sufficiently low normal organ exposure. Affibody molecules are minimized protein domains with very high tumor targeting capacity as demonstrated in recent trials with HER2 targeting tezatabep matraxetan in patients with metastatic breast cancer. The HER2 binder has in recent development been engineered for reduced kidney uptake and improved tumor load resulting in a radiotherapeutic drug which is currently in late IND-enabling studies. Preclinical development and theranostic patient selection will be discussed.

Increased expression of CXCR4 has been observed in benign adrenal tumors and in over 20 malignant cancers. Our clinical pipeline includes PentixaTher, a Yttrium-90 based therapeutic, and PentixaFor, a Gallium-68 based companion diagnostic. We will present how we are using both as a theranostic pair in oncology and highlight the potential of PentixaFor outside of oncology as a diagnostic tool for primary aldosteronism (PA), an important cause of hypertension.