Targeted thorium-227 conjugates as treatment options in oncology

Area of Science:

• Oncology
• Nuclear Medicine
• Radiopharmaceutical Therapy

Background:

• Targeted alpha therapy (TAT) leverages unique properties of alpha-emitters for cancer treatment, including high linear energy transfer (LET) and localized cell killing.
• Existing alpha therapies like radium-223 dichloride are limited in their ability to be conjugated with targeting moieties.
• Several alpha radionuclides, including actinium-225 and thorium-227, are under investigation for their therapeutic potential.

Purpose of the Study:

• To explore the potential of thorium-227 conjugates (TTCs) as a versatile platform for targeted alpha therapy.
• To evaluate the efficacy and applicability of TTCs in various cancer types and in combination with other anti-cancer agents.

Main Methods:

• Conjugation of tumor-targeting modalities (antibodies, small molecules) with chelators for subsequent radiolabeling with alpha-emitters, specifically thorium-227.
• Pre-clinical studies evaluating TTCs against tumor cells expressing specific antigens.
• Investigation of combination therapies involving TTCs with androgen receptor inhibitors, DNA damage response inhibitors, and immune checkpoint inhibitors.

Main Results:

• Thorium-227 can be readily chelated, enabling the development of targeted thorium conjugates (TTCs) for broad tumor targeting.
• TTCs have demonstrated promise in pre-clinical models and early clinical activity in hematological malignancies targeting CD22.
• Pre-clinical data suggest additive or synergistic effects when TTCs are combined with established anti-cancer therapies.

Conclusions:

• Targeted thorium conjugates represent a promising advancement in targeted alpha therapy, overcoming limitations of existing agents.
• The ability to chelate thorium-227 facilitates targeted delivery and opens avenues for combination strategies in oncology.
• Further clinical development of TTCs holds significant potential for improving cancer treatment outcomes.