Radiotheranostic Pair Could Identify and Treat Kidney Tumors

A newly developed radiotheranostic pair, ⁶⁸Ga/¹⁷⁷Lu-NYM096,  can identify tumors and effectively deliver targeted radiotherapy to patients with metastatic clear cell renal cell carcinoma (ccRCC). Using a small molecule compound, the new approach helps to mitigate toxicity issues common with treatment, offering a safe and feasible strategy for those with end-stage disease. This research was published in the September issue of The Journal of Nuclear Medicine.

 ccRCC is the most common subtype of renal cancer, accounting for approximately 70 to 80 percent of all cases. Many patients have unresectable or metastatic disease upon initial diagnosis or develop advanced-stage disease after initial localized treatment. While immunotherapy-based combination therapies have emerged as effective treatment strategies, a notable proportion of patients don’t respond to therapy or experience significant toxicities.

“My colleagues and I developed a new generation of small molecule compounds that target carbonic anhydrase IX (CAIX) enzymes which are overexpressed in ccRCC,” said Wenjia Zhu, MD, associate professor in the Department of Nuclear Medicine at Peking Union Medical College Hospital in Beijing, China. “These compounds allow for radiolabeling with both diagnostic and therapeutic radioisotopes to more precisely—and safely—deliver treatment to patients.”

Researchers conducted preclinical and first-in-human experiments to explore the characteristics of the theranostic pair ⁶⁸Ga/¹⁷⁷Lu-NYM096, focusing on its safety, tolerability, dosimetry, and preliminary efficacy for metastatic ccRCC. First, in vivo biodistribution of ⁶⁸Ga-NYM096 and the therapeutic efficacy of ¹⁷⁷Lu-NYM096 was evaluated in ccRCC-tumor bearing mice. Next, patients with metastatic ccRCC who had disease progression after standard therapy underwent serial whole-body ⁶⁸Ga-NYM096 PET/CT to evaluate biodistribution and dosimetry. Those with positive CAIX expression received ¹⁷⁷Lu-NYM096 following a standard 3-plus-3 dose escalation design. Serial whole-body planar imaging was performed after the first therapy cycle. Safety, dosimetry, and preliminary efficacy were evaluated. 

In the murine models, high tumor accumulation of ⁶⁸Ga/¹⁷⁷Lu-NYM096 was observed. ¹⁷⁷Lu-NYM096 was well tolerated and demonstrated a significant dose-dependent tumor suppression effect. In patients, ⁶⁸Ga-NYM096 demonstrated excellent tumor uptake and ¹⁷⁷Lu-NYM096 treatment demonstrated no evidence of nephrotoxicity, hepatotoxicity, or pancreatic toxicity. Gastric toxicity, however, was observed. Follow-up ⁶⁸Ga-NYM096 PET/CT evaluations showed evidence of tumor response to ¹⁷⁷Lu-NYM096 treatment. 

“Our imaging agent identified tumors with very high uptake, and our early clinical experience suggests that targeted radiotherapy may offer a new treatment strategy for selected patients,” noted Li Huo, MD, director of the Department of Nuclear Medicine at Peking Union Medical College Hospital in Beijing, China. “This study provides the first human evidence of both the promise of this approach and highlights an important challenge—radiation to the stomach-that will help guide the development of safer future treatments.”