Residency · Residency · Nuclear Medicine

Emerging Theranostic Targets and Agents

Introduction

Theranostics combines diagnostic imaging with targeted radionuclide therapy, creating a paradigm where the same molecular target is used for both visualization and treatment. Building on the success of Lu-177 DOTATATE for neuroendocrine tumors and Lu-177 PSMA-617 for prostate cancer, the field is rapidly expanding to new molecular targets, novel radiopharmaceuticals, and innovative combination strategies that promise to extend the theranostic approach to a much broader range of cancers.

Principles of Theranostic Design

Target Selection Criteria

The ideal theranostic target demonstrates a high tumor-to-background ratio for both imaging and therapeutic dose delivery. It should be overexpressed on tumor cells relative to normal tissues. For alpha emitters, the target does not necessarily need to internalize, but internalization is preferred for beta emitters to maximize intracellular radiation delivery. The targeting molecule must be stable in vivo with favorable pharmacokinetics and biodistribution and must be amenable to labeling with both diagnostic and therapeutic radionuclides.

Diagnostic-Therapeutic Radionuclide Pairs

The Ga-68/Lu-177 pair is the most established combination, using PET imaging for diagnosis followed by beta therapy. Ga-68/Ac-225 pairs PET imaging with alpha-particle therapy for more potent cell killing. Cu-64/Cu-67 represents a true theranostic pair from the same element, offering elegant chemistry. Zr-89/Y-90 enables immuno-PET imaging paired with beta therapy using antibody-based vectors. I-124/I-131 allows PET/CT dosimetry followed by beta therapy for iodine-avid targets.

Novel Theranostic Targets

Fibroblast Activation Protein (FAP)

FAP is overexpressed in the tumor microenvironment across multiple malignancies, representing a fundamentally different approach from targeting tumor cells directly. Ga-68 FAPI PET/CT demonstrates high uptake in breast, pancreatic, and sarcoma subtypes among others. Lu-177 FAPI and Ac-225 FAPI are under clinical investigation for therapeutic applications. The potential advantage of FAP targeting is pan-cancer applicability with low background uptake in most normal tissues.

CXCR4

CXCR4 is a chemokine receptor overexpressed in hematologic malignancies and certain solid tumors. Ga-68 Pentixafor is used for PET imaging, and Lu-177 Pentixather is the corresponding therapeutic agent. Early clinical trials are evaluating this pair in multiple myeloma, lymphoma, and acute leukemia.

HER2

HER2 is a well-established oncologic target now being explored with radionuclide approaches. Zr-89 trastuzumab enables immuno-PET imaging to visualize HER2 expression across the body. Ac-225-labeled anti-HER2 constructs are in preclinical development for targeted alpha therapy.

Carbonic Anhydrase IX (CAIX)

CAIX is expressed in clear cell renal cell carcinoma. Girentuximab, an anti-CAIX antibody, has been labeled with Zr-89 for diagnostic imaging and Lu-177 for therapy. Phase III trial data support the clinical utility of this approach.

Alpha-Particle Therapy: The Next Frontier

Advantages of Alpha Emitters

Alpha particles have high linear energy transfer ranging from 50 to 230 keV per micrometer, compared to the much lower LET of beta particles. Their short tissue range of 50 to 100 micrometers spares surrounding normal cells while concentrating the radiation dose precisely at the target. Alpha particles are effective independent of oxygenation status, overcoming the hypoxia resistance that limits beta emitter and external beam efficacy in many tumors. Fewer DNA repair mechanisms are effective against the dense double-strand breaks caused by alpha particles.

Key Alpha-Emitting Agents

Ac-225 PSMA-617 is showing promise in mCRPC refractory to Lu-177 PSMA therapy, offering a salvage option for patients who have progressed on beta-emitter treatment. Ra-223 dichloride (Xofigo) is already FDA-approved for bone-metastatic CRPC. At-211 is an ultra-short-half-life alpha emitter being investigated for locoregional therapy applications. Pb-212/Bi-212 generators represent emerging in-vivo generator systems where the parent isotope decays to produce an alpha-emitting daughter at the tumor site.

Pretargeted Radioimmunotherapy

Pretargeted radioimmunotherapy separates antibody delivery from radionuclide administration, solving the problem of prolonged circulation times that expose normal organs to radiation when directly radiolabeled antibodies are used. Bispecific antibodies are administered first, binding to the tumor antigen and presenting a binding site for a subsequently administered radiolabeled hapten. This approach reduces radiation exposure to normal organs, especially the bone marrow. Click chemistry approaches using tetrazine/TCO pairs show preclinical promise for efficient in-vivo conjugation.

Combination Strategies

Theranostics combined with immune checkpoint inhibitors may enhance abscopal effects, in which radiation-induced immunogenic cell death triggers systemic immune responses against distant tumor sites. Radiosensitizers such as PARP inhibitors can augment DNA damage from radionuclides by preventing repair of radiation-induced breaks. External beam radiation combined with targeted radionuclide therapy is being explored for synergistic effects. Sequential alpha and beta therapy protocols, administering both types of emitters in a planned sequence, are under investigation.

Challenges and Future Directions

Supply chain limitations for Ac-225 and other alpha emitters remain a significant barrier to widespread clinical use. Standardization of dosimetry for alpha-particle therapy is needed because the short range makes dose estimation fundamentally different from beta emitters. Managing xerostomia and renal toxicity with novel radioligands continues to be a challenge. Randomized controlled trials comparing theranostic approaches to standard therapies are needed for regulatory approval and guideline development. Artificial intelligence is being applied to target identification, treatment planning, and dosimetry optimization.

Clinical Pearls

The ideal theranostic target exhibits high tumor expression, low normal-tissue expression, and compatibility with both imaging and therapeutic radionuclides. Evaluating these properties is the first step in developing any new theranostic program.

Alpha-particle emitters like Ac-225 offer potential salvage therapy for patients who progress on beta-emitting agents such as Lu-177. Their high LET and short range make them particularly effective against micrometastases and radioresistant tumors.

FAP-targeted theranostics represent a paradigm shift by targeting the tumor microenvironment rather than tumor cells directly, offering pan-cancer applicability that could extend theranostics beyond the current niche of neuroendocrine tumors and prostate cancer.

Pretargeted radioimmunotherapy decouples antibody pharmacokinetics from radiation delivery, substantially reducing hematologic toxicity and enabling the use of short-lived radionuclides with antibody-based targeting.

References

1. Kratochwil C, et al. "Ga-68-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers." J Nucl Med. 2019;60(3):386-392.
2. Sathekge M, et al. "Ac-225-PSMA-617 in Chemotherapy-Naive Patients with Advanced Prostate Cancer." Eur J Nucl Med Mol Imaging. 2019;46(1):129-138.
3. Herrmann K, et al. "Radiotheranostics: A Roadmap for Future Development." Lancet Oncol. 2020;21(3):e146-e156.
4. Lütje S, et al. "Pretargeted Radioimmunotherapy: Current Status and Future Directions." Semin Nucl Med. 2021;51(6):584-594.

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