177Lu-Labeled Antibody-Drug Conjugate: A Dual-Mechanistic Treatment Modality in Solid Tumors

Area of Science:

• Oncology
• Radiopharmaceutical Therapy
• Drug Development

Background:

• Antibody-drug conjugates (ADCs) are emerging therapeutics for cancer treatment.
• Site-selective radiolabeling offers improved homogeneity and defined drug-to-antibody ratios.
• Lutetium-177 (177Lu) is a clinically relevant radioisotope for targeted radionuclide therapy.

Purpose of the Study:

• To evaluate the efficacy of site-selective 177Lu-labeled ADCs against solid tumors.
• To compare the performance of site-selective ADCs with conventional radioimmunoconjugates (RICs).
• To explore the potential of these agents as a dual-mechanistic treatment modality.

Main Methods:

• Construction and characterization of site-selective 177Lu-labeled ADCs (anti-TROP2 and anti-HER2) and RICs.
• Biodistribution studies in xenograft mouse models bearing orthotopic breast tumors.
• In vivo therapeutic efficacy studies in refractory breast tumor models.

Main Results:

• Site-selective 177Lu-labeled ADCs and homogeneous RICs exhibited high homogeneity and defined chelator/payload-to-antibody ratios.
• 177Lu-DTPA TROP2 ADC and anti-TROP2 homogeneous RIC demonstrated significantly higher radioactivity accumulation in TROP2-expressing tumors.
• 177Lu-DTPA TROP2 ADC significantly suppressed tumor growth compared to anti-TROP2 homogeneous RIC.
• Anti-HER2 177Lu-DO3A ADC showed superior efficacy in a refractory HER2-expressing breast tumor model.

Conclusions:

• Site-selective 177Lu-labeled ADCs are effective in treating refractory solid tumors, including those with heterogeneous antigen expression.
• These agents represent a promising single-agent, dual-mechanistic treatment modality for solid tumors.
• Further exploration of site-selective radiolabeled ADCs is warranted for clinical application.