CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer.


Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor for which there are no screening methods sensitive enough to facilitate early, effective intervention. We propose targeting the neuroendocrine tumor neoantigen CD133 via antibody-based early detection and PET (immunoPET) to facilitate earlier and more accurate detection of SCLC. <b>Methods:</b> RNA sequencing datasets, immunohistochemistry, flow cytometry, and Western blots were used to quantify CD133 expression in healthy and SCLC patients. CD133 was imaged <i>in vivo</i> using near-infrared fluorescence (NIRF) immunoimaging, and <sup>89</sup>Zr immunoPET. Anti(α)-CD133 autoantibody levels were measured in SCLC patient plasma using antibody microarrays. <b>Results:</b> Across 6 publicly available datasets, CD133 messenger RNA was found to be higher in SCLC tumors than in other tissues, including healthy or normal adjacent lung and non-SCLC samples. Critically, the upregulation of CD133 messenger RNA in SCLC was associated with a significant increase (hazard ratio, 2.62) in death. CD133 protein was expressed in primary human SCLC, in SCLC patient-derived xenografts, and in both SCLC cell lines tested (H82 and H69). Using an H82 xenograft mouse model, we first imaged CD133 expression with NIRF. Both <i>in vivo</i> and <i>ex vivo</i> NIRF clearly showed that a fluorophore-tagged αCD133 homed to lung tumors. Next, we validated the noninvasive visualization of subcutaneous and orthotopic H82 xenografts via immunoPET. An αCD133 antibody labeled with the positron-emitting radiometal <sup>89</sup>Zr demonstrated significant accumulation in tumor tissue while producing minimal uptake in healthy organs. Finally, plasma αCD133 autoantibodies were found in subjects from cohort studies up to 1 year before SCLC diagnosis. <b>Conclusion:</b> In light of these findings, we conclude that the presence of αCD133 autoantibodies in a blood sample followed by CD133-targeted <sup>89</sup>Zr-immunoPET could be an effective early detection screening strategy for SCLC.

  • Fitzpatrick AL
  • Houghton AM
  • Keinänen O
  • Kunihiro AG
  • Lampe PD
  • Lastwika KJ
  • Li CI
  • Pisarenko T
  • Rodriguez C
  • Sarrett SM
  • Solan JL
  • Taverne LR
  • Zeglis BM
Pub Med ID
Appears In
J Nucl Med, 2022, 63 (11)