Therapeutic Efficacy of C-Kit-Targeted Radioimmunotherapy Using 90Y-Labeled Anti-C-Kit Antibodies in a Mouse Model of Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive tumor and prognosis remains poor. Therefore, the development of more effective therapy is needed. We previously reported that high levels of an anti-c-kit antibody (12A8) accumulated in SCLC xenografts. In the present study, we evaluated the efficacy of two antibodies (12A8 and 67A2) for radioimmunotherapy (RIT) of an SCLC mouse model by labeling with the 90Y isotope.Methods 111In- or 125I-labeled antibodies were evaluated in vitro by cell binding, competitive inhibition and cellular internalization assays in c-kit-expressing SY cells and in vivo by biodistribution in SY-bearing mice. Therapeutic efficacy of 90Y-labeled antibodies was evaluated in SY-bearing mice upto day 28 and histological analysis was conducted at day 7.Results[111In]12A8 and [111In]67A2 specifically bound to SY cells with high affinity (8.0 and 1.9 nM, respectively). 67A2 was internalized similar to 12A8. High levels of [111In]12A8 and [111In]67A2 accumulated in tumors, but not in major organs. [111In]67A2 uptake by the tumor was 1.7 times higher than for [111In]12A8. [90Y]12A8, but not [90Y]67A2, suppressed tumor growth in a dose-dependent manner. Tumors treated with 3.7 MBq of [90Y]12A8, and 1.85 and 3.7 MBq of [90Y]67A2 (absorbed doses were 21.0, 18.0 and 35.9 Gy, respectively) almost completely disappeared approximately 2 weeks after injection, and regrowth was not observed except for in one mouse treated with 1.85 MBq [90Y]67A2. The area of necrosis and fibrosis increased depending on the RIT effect. Apoptotic cell numbers increased with increased doses of [90Y]12A8, whereas no dose-dependent increase was observed following [90Y]67A2 treatment. Body weight was temporarily reduced but all mice tolerated the RIT experiments well.ConclusionTreatment with [90Y]12A8 and [90Y]67A2 achieved a complete therapeutic response when SY tumors received an absorbed dose greater than 18 Gy and thus are promising RIT agents for metastatic SCLC cells at distant sites.

Radioimmunotherapy of pancreatic cancer xenografts in nude mice using 90Y-labeled anti-α6β4 integrin antibody

“…90 Y emits β-particles with a mean emitted energy of 0.9331 MeV, therefore the mean energy emitted per transition was calculated as 1.496 × 10 −13 Gy kg (Bq s) −1 , since 1 eV is equal to 1.602 × 10 −19 J [36]. The calculation procedure of absorbed dose from the biodistribution data was previously described for other radiolabeled antibodies [37]. Briefly, tumor uptake at various time points was plotted against time, and the area under the curve (AUC) was calculated.…”

Neutralization of KIT Oncogenic Signaling in Leukemia with Antibodies Targeting KIT Membrane Proximal Domain 5

“…To our knowledge, within anti-KIT antibodies published or commercially available, of mouse or human KIT specificity, none was described to mediate ADCC or CDC (30, 48) which probably explains the mild toxicity observed in animal models where anti-KIT antibodies were injected (48, 49). Together with the fact that in GIST patients, long term treatment with imatinib does not induce profound hematological toxicity, these observations let anticipate that treatment with KIT specific inhibitory antibodies will not elicit strong toxic secondary effects.…”

“…Recent studies reported pre-clinical data in GIST using naked anti-KIT mAb either competing with SCF (28) or targeting KIT D4 dimerization domain (29). A radiolabelled anti-KIT antibody was also shown to decrease SCLC progression in a mouse model (30). …”

αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-cyclam-RAFT-c(-RGDfK-)4

“…From the biodistribution data, the tumor and organ time-activity curves were plotted and the AUCs were calculated for representing the residence time of the injected radiocompound. The absorbed doses were calculated according to the formula AUC Â MEEPT Â injected activity (37).…”